Pharmaceutical compositions comprising bi-1356 and metformin

ABSTRACT

The present invention relates to therapeutic uses of pharmaceutical compositions or combinations of a DPP-4 inhibitor with metformin.

The present invention relates to certain therapeutic uses of acombination comprising a certain DPP-4 inhibitor and metformin, such ase.g. for treating and/or preventing metabolic diseases, especially type2 diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications).

Type 2 diabetes mellitus is a common chronic and progressive diseasearising from a complex pathophysiology involving the dual endocrineeffects of insulin resistance and impaired insulin secretion. Thetreatment of type 2 diabetes typically begins with diet and exercise,followed by oral antidiabetic monotherapy, and although conventionalmonotherapy may initially control blood glucose in some patients, it ishowever associated with a high secondary failure rate. The limitationsof single-agent therapy for maintaining glycemic control may beovercome, at least in some patients, and for a limited period of time bycombining multiple drugs to achieve reductions in blood glucose thatcannot be sustained during long-term therapy with single agents.Available data support the conclusion that in most patients with type 2diabetes current monotherapy will fail and treatment with multiple drugswill be required.

But, because type 2 diabetes is a progressive disease, even patientswith good initial responses to conventional combination therapy willeventually require an increase of the dosage or further treatment withinsulin because the blood glucose level is very difficult to maintainstable for a long period of time. Although existing combination therapyhas the potential to enhance glycemic control, it is not withoutlimitations (especially with regard to long term efficacy). Further, thetraditional combinations have shown an increased risk for side effects,such as hypoglycemia or weight gain.

Thus, for many patients, these existing drug therapies result inprogressive deterioriation in glycemic control despite treatment and donot sufficiently control glycemia especially over long-term and thusfail to achieve and to maintain metabolic control in advanced or latestage type 2 diabetes, including diabetes with inadequate glycemiccontrol despite conventional oral or non-oral antidiabetic medication.

Therefore, although intensive treatment of hyperglycemia can reduce theincidence of chronic damages, many patients with type 2 diabetes remaininadequately treated, partly because of limitations in long termefficacy, tolerability and dosing inconvenience of conventionalantihyperglycemic therapies, patients' poor adherence or comorbidities.

This high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and makrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cardiovascular orcerebrovascular complications such as myocardial infarction, stroke ordeath) in patients with type 2 diabetes.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, glinides and α-glucosidaseinhibitors.

Non-oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, GLP-1 or GLP-1analogues, and insulin or insulin analogues.

However, the use of these conventional antidiabetic or antihyperglycemicagents can be associated with various adverse effects. For example,metformin can be associated with lactic acidosis or gastrointestinalside effects; sulfonylureas, glinides and insulin or insulin analoguescan be associated with hypoglycemia and weight gain; thiazolidinedionescan be associated with edema, bone fracture, weight gain and heartfailure/cardiac effects; and alpha-glucosidase blockers and GLP-1 orGLP-1 analogues can be associated with gastrointestinal adverse effects(e.g. dyspepsia, flatulence or diarrhea, or nausea or vomiting).

Therefore, it remains a need in the art to provide efficacious, safe andtolerable antidiabetic therapies both for patients who have notpreviously been treated with an antidiabetic drug (drug-naïve patients)and for patients with advanced or late stage type 2 diabetes mellitus,including patients with inadequate glycemic control on conventional oraland/or non-oral antidiabetic drugs, such as e.g. metformin,sulphonylureas, thiazolidinediones, glinides and/or α-glucosidaseinhibitors, and/or GLP-1 or GLP-1 analogues, and/or insulin or insulinanalogues.

Further, within the therapy of type 2 diabetes it is a need for treatingthe condition effectively, avoiding the complications inherent to thecondition, and delaying disease progression.

Furthermore, it remains a need that antidiabetic treatments not onlyprevent the long-term complications often found in advanced stages ofdiabetes disease, but also are a therapeutic option in those diabetespatients who have developed complications, such as renal impairment.

Moreover, it remains a need to provide prevention or reduction of riskfor adverse effects associated with conventional antidiabetic therapies.

Within the scope of the present invention it has now been found thatcertain DPP-4 inhibitors as defined herein as well as combinations orpharmaceutical compositions according to this invention of these DPP-4inhibitors with metformin have unexpected and particularly advantageousproperties, which make them suitable for the purpose of this inventionand/or for fulfilling one or more of above needs, such as e.g. forimproving glycemic control as well as for treating and/or preventing(including slowing the progression or delaying the onset) of metabolicdiseases, particularly diabetes (especially type 2 diabetes mellitus)and conditions related thereto (e.g. diabetic complications), in drugnaïve type 2 diabetes patients and/or in patients with advanced or latestage type 2 diabetes, including patients with insufficient glycemiccontrol despite a therapy with an oral and/or a non-oral antidiabetic orantihyperglycemic drug and/or with indication on insulin.

The present invention thus relates to a combination or a pharmaceuticalcomposition comprising a certain DPP-4 inhibitor (particularly BI 1356)and metformin for simultaneous, separate or sequential use in thetherapies described herein.

The present invention also relates to a fixed or free combination orpharmaceutical composition comprising or made of

a certain DPP-4 inhibitor ((particularly BI 1356)) and metformin each asdefined herein, and optionally one or more pharmaceutically acceptablecarriers and/or auxiliaries (including excipients, stabilizers or thelike), for therapeutic uses as described herein, such as e.g. forimproving glycemic control and/or for use in treating and/or preventing(including slowing the progression and/or delaying the onset) ofmetabolic diseases, especially type 2 diabetes mellitus and conditionsrelated thereto (e.g. diabetic complications),either as first line therapy, i.e. in type 2 diabetes patients who havenot previously treated with an antihyperglycemic agent (drug-naïvepatients),or as second or third line therapy, i.e. in type 2 diabetes patientswith insufficient glycemic control despite therapy with one or twoconventional antihyperglycemic agents selected from metformin,sulphonylureas, thiazolidinediones (e.g. pioglitazone), glinides,alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin orinsulin analogues;optionally in combination with one or more other active substances, suchas e.g. any of those mentioned herein,such as e.g. optionally in combination with one conventionalantihyperglycemic agent selected from sulphonylureas, thiazolidinediones(e.g. pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 orGLP-1 analogues, and insulin or insulin analogues.

The present invention also relates to therapeutic uses as describedherein of a pharmaceutical composition according to this inventioncomprising a fixed dose combination formulation of a DPP-4 inhibitordrug and the partner drug metformin.

In one embodiment, the present invention also relates to a fixed or freecombination or pharmaceutical composition as described herein before andherein after, optionally in combination with one conventionalantihyperglycemic agent selected from sulphonylureas,thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1analogues, and insulin or insulin analogues,

for use in treating and/or preventing (including slowing the progressionand/or delaying the onset) of metabolic diseases, especially type 2diabetes mellitus and conditions related thereto (e.g. diabeticcomplications),either as first line therapy, i.e. in type 2 diabetes patients who havenot previously treated with an antihyperglycemic agent (drug-naïvepatients),or as second or third line therapy, i.e. in type 2 diabetes patientswith insufficient glycemic control despite therapy with one or twoconventional antihyperglycemic agents selected from metformin,sulphonylureas, thiazolidinediones, glinides, alpha-glucosidaseblockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

In a particular embodiment, the present invention relates to apharmaceutical composition as described herein, for use in treatingand/or preventing (including slowing the progression and/or delaying theonset) of metabolic diseases, especially type 2 diabetes mellitus andconditions related thereto (e.g. diabetic complications), in type 2diabetes patients with insufficient glycemic control despitemono-therapy with metformin.

In another particular embodiment, the present invention also relates toa pharmaceutical composition as described herein, in combination with asulphonylurea, for use in treating and/or preventing (including slowingthe progression and/or delaying the onset) of metabolic diseases,especially type 2 diabetes mellitus and conditions related thereto (e.g.diabetic complications), in type 2 diabetes patients with insufficientglycemic control despite dual combination therapy with metformin and asulphonylurea.

In another particular embodiment, the present invention also relates toa pharmaceutical composition as described herein, in combination with athiazolidinedione (e.g. pioglitazone), for use in treating and/orpreventing (including slowing the progression and/or delaying the onset)of metabolic diseases, especially type 2 diabetes mellitus andconditions related thereto (e.g. diabetic complications), in type 2diabetes patients with insufficient glycemic control despite dualcombination therapy with metformin and a thiazolidinedione (e.g.pioglitazone).

In another particular embodiment, the present invention also relates toa pharmaceutical composition as described herein, for use in treatingand/or preventing (including slowing the progression and/or delaying theonset) of metabolic diseases, especially type 2 diabetes mellitus andconditions related thereto (e.g. diabetic complications), in drug-naïvetype 2 diabetes patients (e.g. as first line therapy), such as e.g. asearly or initial combination therapy.

The present invention further provides the use of a pharmaceuticalcomposition as defined herein for the manufacture of a medicament fortreating and/or preventing metabolic diseases, particularly type 2diabetes mellitus and conditions related thereto (e.g. diabeticcomplications), e.g. as first, second or third line therapy as describedherein.

The present invention further provides a pharmaceutical packagecomprising a pharmaceutical composition as defined herein and optionallyinstructions for its use, optionally in combination with one or moreother active substances, in the treatment and/or prevention of metabolicdiseases, particularly type 2 diabetes mellitus and conditions relatedthereto (e.g. diabetic complications), in drug-naïve patients or inpatients with insufficient glycemic control despite therapy with one ortwo conventional antihyperglycemic agents selected from metformin,sulphonylureas, thiazolidinediones, glinides, alpha-glucosidaseblockers, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

The present invention further provides a medicament for use in thetreatment and/or prevention of metabolic diseases, particularly type 2diabetes mellitus and conditions related thereto (e.g. diabeticcomplications), in drug-naïve patients or in patients with insufficientglycemic control despite therapy with one or two conventionalantihyperglycemic agents selected from metformin, sulphonylureas,thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1analogues, and insulin or insulin analogues; said medicament comprisinga pharmaceutical composition as defined herein and optionally one ormore other active substances, such as e.g. any of those mentionedherein, such as e.g. for separate, sequential, simultaneous, concurrentor chronologically staggered use of the active ingredients.

The present invention further provides a method of treating and/orpreventing metabolic diseases, particularly type 2 diabetes mellitus andconditions related thereto (e.g. diabetic complications), in drug-naïvepatients (e.g. as first line therapy) or in patients with insufficientglycemic control despite therapy with one or two conventionalantihyperglycemic agents selected from metformin, sulphonylureas,thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or GLP-1analogues, and insulin or insulin analogues (e.g. as second or thirdline therapy); said method comprising administering to a subject in needthereof (particularly a human patient) an effective amount of apharmaceutically composition as defined herein, optionally alone or incombination, such as e.g. separately, sequentially, simultaneously,concurrently or chronologically staggered, with an effective amount ofone or more other active substances, such as e.g. any of those mentionedherein.

The present invention further provides the use of a pharmaceuticalcombination or composition as defined herein before and herein aftercomprising BI 1356 and metformin, for the manufacture of a medicamentfor one or more of the following purposes:

-   -   preventing, slowing the progression of, delaying the onset of or        treating a metabolic disorder or disease, such as e.g. type 1        diabetes mellitus, type 2 diabetes mellitus, impaired glucose        tolerance (IGT), impaired fasting blood glucose (IFG),        hyperglycemia, postprandial hyperglycemia, overweight, obesity,        dyslipidemia, hyperlipidemia, postprandial hyperlipidemia,        hypercholesterolemia, hypertension, atherosclerosis, endothelial        dysfunction, osteoporosis, chronic systemic inflammation,        non-alcoholic fatty liver disease (NAFLD), retinopathy,        neuropathy, nephropathy, polycystic ovarian syndrome and/or        metabolic syndrome;    -   improving and/or maintaining glycemic control and/or for        reducing of fasting plasma glucose, of postprandial plasma        glucose and/or of glycosylated hemoglobin HbA1c;    -   preventing, slowing, delaying the onset of or reversing        progression from impaired glucose tolerance (IGT), impaired        fasting blood glucose (IFG), insulin resistance and/or from        metabolic syndrome to type 2 diabetes mellitus;    -   preventing, reducing the risk of, slowing the progression of,        delaying the onset of or treating of complications of diabetes        mellitus such as micro- and macrovascular diseases, such as        nephropathy, micro- or macroalbuminuria, proteinuria,        retinopathy, cataracts, neuropathy, learning or memory        impairment, neurodegenerative or cognitive disorders, cardio- or        cerebrovascular diseases, tissue ischaemia, diabetic foot or        ulcus, atherosclerosis, hypertension, endothelial dysfunction,        myocardial infarction, acute coronary syndrome, unstable angina        pectoris, stable angina pectoris, peripheral arterial occlusive        disease, cardiomyopathy, heart failure, heart rhythm disorders,        vascular restenosis, and/or stroke;    -   reducing body weight and/or body fat or preventing an increase        in body weight and/or body fat or facilitating a reduction in        body weight and/or body fat;    -   preventing, slowing the progression of, delaying the onset of or        treating the degeneration of pancreatic beta cells and/or the        decline of the functionality of pancreatic beta cells and/or for        improving, preserving and/or restoring the functionality of        pancreatic beta cells and/or stimulating and/or restoring or        protecting the functionality of pancreatic insulin secretion        and/or increasing pancreatic beta cell mass;    -   preventing, slowing the progression of, delaying the onset of or        treating non alcoholic fatty liver disease (NAFLD) including        hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or        liver fibrosis (such as e.g. preventing, slowing the        progression, delaying, attenuating, treating or reversing        hepatic steatosis, (hepatic) inflammation and/or an abnormal        accumulation of liver fat);    -   preventing, slowing the progression of, delaying the onset of or        treating type 2 diabetes with primary or secondary failure to        conventional (oral or non-oral) antihyperglycemic mono- or        combination therapy or delaying the need for insulin treatment;    -   achieving a reduction in the dose of conventional        antihyperglycemic medication required for adequate therapeutic        effect;    -   reducing the risk for adverse effects associated with        conventional antihyperglycemic medication; and/or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;        particularly either in a drug-naïve type 2 diabetes patient or        in a type 2 diabetes patient with insufficient glycemic control        despite therapy with one or two conventional antihyperglycemic        agents selected from metformin, sulphonylureas,        thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1        or GLP-1 analogues, and insulin or insulin analogues; optionally        in combination with one or more other active substances, such as        e.g. any of those mentioned herein.

In a particular embodiment, the present invention provides a method oftreating and/or preventing metabolic diseases, particularly type 2diabetes mellitus and conditions related thereto (e.g. diabeticcomplications), in drug-naïve patients (e.g. as first line therapy);said method comprising administering to a subject in need thereof(particularly a human patient) an effective amount of a pharmaceuticallycomposition of BI 1356 and metformin according to this invention.

In another particular embodiment, the present invention provides amethod of treating and/or preventing metabolic diseases, particularlytype 2 diabetes mellitus and conditions related thereto (e.g. diabeticcomplications), in patients with insufficient glycemic control despitemono-therapy with metformin (e.g. as second line therapy); said methodcomprising administering to a subject in need thereof (particularly ahuman patient) an effective amount of a pharmaceutically composition ofBI 1356 and metformin according to this invention.

In another particular embodiment, the present invention provides amethod of treating and/or preventing metabolic diseases, particularlytype 2 diabetes mellitus and conditions related thereto (e.g. diabeticcomplications), in patients with insufficient glycemic control despitedual combination therapy with metformin and a thiazolidinedione (e.g. asthird line therapy); said method comprising administering to a subjectin need thereof (particularly a human patient) an effective amount of apharmaceutically composition of BI 1356 and metformin according to thisinvention, and a thiazolidinedione.

In another particular embodiment, the present invention provides amethod of treating and/or preventing metabolic diseases, particularlytype 2 diabetes mellitus and conditions related thereto (e.g. diabeticcomplications), in patients with insufficient glycemic control despitedual combination therapy with metformin and a sulphonylurea (e.g. asthird line therapy); said method comprising administering to a subjectin need thereof (particularly a human patient) an effective amount of apharmaceutically composition of BI 1356 and metformin according to thisinvention, and a sulphonylurea.

In a further embodiment, the present invention provides a method oftreating and/or preventing metabolic diseases, particularly type 2diabetes mellitus and conditions related thereto (e.g. diabeticcomplications), in patients with insufficient glycemic control despitedual combination therapy with metformin and insulin or insulin analog;said method comprising administering to a subject in need thereof(particularly a human patient) an effective amount of a pharmaceuticallycomposition of BI 1356 and metformin according to this invention, andinsulin or insulin analog.

In a further embodiment, the present invention provides a method oftreating and/or preventing metabolic diseases, particularly type 2diabetes mellitus and conditions related thereto (e.g. diabeticcomplications), in patients treated with insulin or insulin analog; saidmethod comprising administering to a subject in need thereof(particularly a human patient) an effective amount of a pharmaceuticallycomposition of BI 1356 and metformin according to this invention,thereby replacing said insulin or insulin analog (i.e. switching frominsulin therapy to a BI 1356 & metformin combination according to thisinvention).

Examples of such metabolic diseases or disorders amenable to the therapyof this invention may include, without being restricted to, Type 1diabetes, Type 2 diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypercholesterolemia,dyslipidemia, metabolic syndrome X, obesity, hypertension, chronicsystemic inflammation, non-alcoholic fatty liver disease (NAFLD),retinopathy, neuropathy, nephropathy, atherosclerosis, endothelialdysfunction and osteoporosis.

In the monitoring of the treatment of diabetes mellitus the HbA1c value,the product of a non-enzymatic glycation of the haemoglobin B chain, isof exceptional importance. As its formation depends essentially on theblood sugar level and the life time of the erythrocytes the HbA1c in thesense of a “blood sugar memory” reflects the average blood sugar levelof the preceding 4-12 weeks. Diabetic patients whose HbA1c level hasbeen well controlled over a long time by more intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample) aresignificantly better protected from diabetic microangiopathy. Theavailable treatments for diabetes can give the diabetic an averageimprovement in their HbA1c level of the order of 1.0-1.5%. Thisreduction in the HbA1C level is not sufficient in all diabetics to bringthem into the desired target range of <7.0%, preferably <6.5% and morepreferably <6% HbA1c.

Within glycemic control, in addition to improvement of the HbA1c level,other recommended therapeutic goals for type 2 diabetes mellituspatients are improvement of fasting plasma glucose (FPG) and ofpostprandial plasma glucose (PPG) levels to normal or as near normal aspossible. Recommended desired target ranges of preprandial (fasting)plasma glucose are 90-130 mg/dL (or 70-130 mg/dL) or <110 mg/dL, and oftwo-hour postprandial plasma glucose are <180 mg/dL or <140 mg/dL.

Within the meaning of this invention, inadequate or insufficientglycemic control means in particular a condition wherein patients showHbA1c values above 6.5%, in particular above 7.0%, even more preferablyabove 7.5%, especially above 8%. An embodiment of patients withinadequate or insufficient glycemic control include, without beinglimited to, patients having a HbA1c value from 7.5 to 10% (or, inanother embodiment, from 7.5 to 11%). Another embodiment of patientswith inadequate or insufficient glycemic control include, without beinglimited to, patients having HbA1c value from 6.5 to 8.4% (stage 1), or,in yet another embodiment, from 8.5 to 9.4% (stage 2), or, in still yetanother embodiment, 9.5% (stage 3). A special sub-embodiment ofinadequately controlled patients refers to patients with poor glycemiccontrol including, without being limited, patients having a HbA1c value90%.

In one embodiment, diabetes patients within the meaning of thisinvention may include patients who have not previously been treated withan antidiabetic drug (drug-naïve patients). Thus, in an embodiment, thetherapies described herein may be used in naïve patients. In anotherembodiment, diabetes patients within the meaning of this invention mayinclude patients with advanced or late stage type 2 diabetes mellitus(including patients with failure to conventional antidiabetic therapy),such as e.g. patients with inadequate glycemic control on one, two ormore conventional oral and/or non-oral antidiabetic drugs as definedherein, such as e.g. patients with insufficient glycemic control despite(mono-)therapy with metformin, a thiazolidinedione (particularlypioglitazone), a sulphonylurea, a glinide, GLP-1 or GLP-1 analogue,insulin or insulin analogue, or an α-glucosidase inhibitor, or despitedual combination therapy with metformin/sulphonylurea,metformin/thiazolidinedione (particularly pioglitazone),sulphonylurea/α-glucosidase inhibitor, pioglitazone/sulphonylurea,metformin/insulin, pioglitazone/insulin or sulphonylurea/insulin. Thus,in an embodiment, the therapies described herein may be used in patientsexperienced with therapy, e.g. with conventional oral and/or non-oralantidiabetic mono- or dual or triple combination medication as mentionedherein.

An embodiment of the patients which may be amenable to the therapies ofthis invention may include, without being limited, those diabetespatients for whom normal metformin therapy is not appropriate, such ase.g. those diabetes patients who need reduced dose metformin therapy dueto reduced tolerability, intolerability or contraindication againstmetformin or due to (mildly) impaired/reduced renal function (includingelderly patients, such as e.g. 60-65 years).

A special embodiment of the DPP-4 inhibitors of this invention refers tothose orally administered DPP-4 inhibitors which are therapeuticallyefficacious at low dose levels, e.g. at dose levels <100 mg or <70 mgper patient per day, preferably <50 mg, more preferably <30 mg or <20mg, even more preferably from 1 mg to 10 mg (if required, divided into 1to 4 single doses, particularly 1 or 2 single doses, which may be of thesame size), particularly from 1 mg to 5 mg (more particularly 5 mg), perpatient per day, preferentially, administered orally once-daily, morepreferentially, at any time of day, administered with or without food.Thus, for example, the daily oral amount 5 mg BI 1356 can be given in aonce daily dosing regimen (i.e. 5 mg BI 1356 once daily) or in a twicedaily dosing regimen (i.e. 2.5 mg BI 1356 twice daily), at any time ofday, with or without food.

A particularly preferred DPP-4 inhibitor to be emphasized within themeaning of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(also known as BI 1356 or linagliptin). BI 1356 exhibits high potency,24 h duration of action, and a wide therapeutic window. In patients withtype 2 diabetes receiving multiple oral doses of 1, 2.5, 5 or 10 mg ofBI 1356 once daily for 12 days, BI 1356 shows favourable pharmacodynamicand pharmacokinetic profile with rapid attainment of steady state (e.g.reaching steady state plasma levels (>90% of the pre-dose plasmaconcentration on Day 13) between second and fifth day of treatment inall dose groups), little accumulation (e.g. with a mean accumulationratio R_(A,AUC)≦1.4 with doses above 1 mg) and preserving a long-lastingeffect on DPP-4 inhibition (e.g. with almost complete (>90%) DPP-4inhibition at the 5 mg and 10 mg dose levels, i.e. 92.3 and 97.3%inhibition at steady state, respectively, and >80% inhibition over a 24h interval after drug intake), as well as significant decrease in 2 hpostprandial blood glucose excursions by 80% (already on Day 1) in doses2.5 mg, and with the cumulative amount of unchanged parent compoundexcreted in urine on Day 1 being below 1% of the administered dose andincreasing to not more than about 3-6% on Day 12 (renal clearanceCL_(R,ss) is from about 14 to about 70 mL/min for the administered oraldoses, e.g. for the 5 mg dose renal clearance is about 70 ml/min). Inpeople with type 2 diabetes BI 1356 shows a placebo-like safety andtolerability (e.g. low risk for hypoglycemia, edema or weight gain).With low doses of about 5 mg, BI 1356 acts as a true once-daily oraldrug with a full 24 h duration of DPP-4 inhibition. At therapeutic oraldose levels, BI 1356 is mainly excreted via the liver and only to aminor extent (about <7% of the administered oral dose) via the kidney.BI 1356 is primarily excreted unchanged via the bile. The fraction of BI1356 eliminated via the kidneys increases only very slightly over timeand with increasing dose, so that there will likely be no need to modifythe dose of BI 1356 based on the patients' renal function. The non-renalelimination of BI 1356 in combination with its low accumulationpotential and broad safety margin may be of significant benefit in apatient population that has a high prevalence of renal insufficiency anddiabetic nephropathy. BI 1356 is suitable for once-daily dosing withoutthe need for dose titration when co-administered with metformin.

In one embodiment, pharmaceutical compositions or fixed dosecombinations of this invention include, without being limited to, suchcompositions which comprise immediate release metformin and linagliptin(preferably linagliptin as an immediate release component). Examples ofsuch compositions include, without being limited, mono-layer tablets,bi-layer tablets, tablets-in-tablets/Bull's eye tablets or drug(linagliptin)-coated tablets (each of which may be optionallyover-coated with a non-functional film-coat), e.g. such tablet forms asdescribed in more detail herein, particularly those given in the examplesection (preferred is hereby the mono-layer tablet of this invention).

In another embodiment, pharmaceutical compositions or fixed dosecombinations of this invention include, without being limited to, suchcompositions which comprise controlled or sustained (e.g. slow orextended) release metformin and linagliptin (preferably linagliptin asan immediate release component). Examples of such compositions include,without being limited, drug (linagliptin)-coated tablets (which may beoptionally over-coated with a non-functional film-coat), e.g.compositions comprising i) an extended release core comprising metforminand one or more suitable excipients and ii) a (preferably immediaterelease) film-coating comprising linagliptin (e.g. such a film-coatlayer as described herein). Examples of slow release include, withoutbeing limited, a metformin composition (e.g. as tablet core) wheremetformin is released at a rate where the peak plasma levels ofmetformin are typically achieved about 8-22 h after administration.

Typical dosage strengths of the dual fixed dose combination (tablet) oflinagliptin/metformin IR (immediate release) are 2.5/500 mg, 2.5/850 mgand 2.5/1000 mg, which may be administered 1-3 times a day, particularlytwice a day.

Typical dosage strengths of the dual fixed dose combination (tablet) oflinagliptin/metformin XR (extended release) are 5/500 mg, 5/1000 mg and5/1500 mg, which may be administered 1-2 times a day, particularly oncea day (preferably to be taken in the evening preferably with meal, e.g.prior to sleep), or 2.5/500, 2.5/750 and 2.5/1000, which may beadministered 1-2 times a day, particularly one or two tablets once a day(preferably to be taken in the evening preferably with meal).

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg per day using various dosing regimens from about 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mgonce or twice a day, or delayed-release metformin in doses of about 100mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day orabout 500 mg to 2000 mg once a day. Particular dosage strengths may be250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.

As different metabolic functional disorders often occur simultaneously,it is quite often indicated to combine a number of different activeprinciples with one another. Thus, depending on the functional disordersdiagnosed, improved treatment outcomes may be obtained if a DPP-4inhibitor or pharmaceutical composition according to this invention iscombined with active substances customary for the respective disorders,such as e.g. one or more active substances selected from among the otherantidiabetic substances, especially active substances that lower theblood sugar level or the lipid level in the blood, raise the HDL levelin the blood, lower blood pressure or are indicated in the treatment ofatherosclerosis or obesity.

The DPP-4 inhibitors or pharmaceutical compositions mentionedherein—besides their use on their own—may also be used in conjunctionwith other active substances, by means of which improved treatmentresults can be obtained. Such a combined treatment may be given as afree combination of the substances or in the form of a fixedcombination, for example in a tablet or capsule. Pharmaceuticalformulations of the combination partner needed for this may either beobtained commercially as pharmaceutical compositions or may beformulated by the skilled man using conventional methods. The activesubstances which may be obtained commercially as pharmaceuticalcompositions are described in numerous places in the prior art, forexample in the list of drugs that appears annually, the “Rote Liste®” ofthe federal association of the pharmaceutical industry, or in theannually updated compilation of manufacturers' information onprescription drugs known as the “Physicians' Desk Reference”.

Examples of antidiabetic combination partners (beyond metformin) aresulphonylureas such as glibenclamide, tolbutamide, glimepiride,glipizide, gliquidon, glibornuride and gliclazide; nateglinide;repaglinide; thiazolidinediones such as rosiglitazone and pioglitazone;PPAR gamma modulators such as metaglidases; PPAR-gamma agonists such asrivoglitazone, mitoglitazone, INT-131 or balaglitazone; PPAR-gammaantagonists; PPAR-gamma/alpha modulators such as tesaglitazar,muraglitazar, aleglitazar, indeglitazar and KRP297;PPAR-gamma/alpha/delta modulators such as e.g. lobeglitazone;AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2)inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors;pancreatic beta cell GCRP agonists such as SMT3-receptor-agonists andGPR119, such as the GPR119 agonists5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidineor5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-2-(4-methanesulfonyl-phenyl)-pyridine;11β-HSD-inhibitors; FGF19 agonists or analogues; alpha-glucosidaseblockers such as acarbose, voglibose and miglitol; alpha2-antagonists;insulin and insulin analogues such as human insulin, insulin lispro,insulin glusilin, r-DNA-insulinaspart, NPH insulin, insulin detemir,insulin degludec, insulin tregopil, insulin zinc suspension and insulinglargin; Gastric inhibitory Peptide (GIP); amylin and amylin analogues(e.g. pramlintide, davalintide); or GLP-1 and GLP-1 analogues such asExendin-4, e.g. exenatide, exenatide LAR, liraglutide, taspoglutide,lixisenatide (AVE-0010), LY-2428757, dulaglutide (LY-2189265),semaglutide or albiglutide; SGLT2-inhibitors such as dapagliflozin,sergliflozin (KGT-1251), atigliflozin, canagliflozin, ipragliflozin ortofogliflozin; inhibitors of protein tyrosine-phosphatase (e.g.trodusquemine); inhibitors of glucose-6-phosphatase;fructose-1,6-bisphosphatase modulators; glycogen phosphorylasemodulators; glucagon receptor antagonists;phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvatedehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976)or of serine/threonine kinase; glucokinase/regulatory protein modulatorsincl. glucokinase activators; glycogen synthase kinase inhibitors;inhibitors of the SH2-domain-containing inositol 5-phosphatase type 2(SHIP2); IKK inhibitors such as high-dose salicylate; JNK1 inhibitors;protein kinase C-theta inhibitors; beta 3 agonists such as ritobegron,YM 178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825;aldosereductase inhibitors such as AS 3201, zenarestat, fidarestat,epalrestat, ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or SGLT-2inhibitors, such as e.g. dapagliflozin, sergliflozin, atigliflozin orcanagliflozin (or compound of formula (I-S) or (I-K) from WO2009/035969); KV 1.3 channel inhibitors; GPR40 modulators such as e.g.[(3S)-6-{(2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]aceticacid; SCD-1 inhibitors; CCR-2 antagonists; dopamine receptor agonists(bromocriptine mesylate [Cycloset]);4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutanoic acid; sirtuinstimulants; and other DPP IV inhibitors.

A dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or dividedtwice) a day (typical dosage strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (up to 40mg divided twice) a day (typical dosage strengths are 5 and 10 mg), orextended-release glipizide in doses from 5 to 10 mg (up to 20 mg) once aday (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

A dual combination of glibenclamide/metformin is usually given in dosesfrom 1.25/250 once daily to 10/1000 mg twice daily (typical dosagestrengths are 1.25/250, 2.5/500 and 5/500 mg).

A dual combination of glipizide/metformin is usually given in doses from2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250,2.5/500 and 5/500 mg).

A dual combination of glimepiride/metformin is usually given in dosesfrom 1/250 to 4/1000 mg twice daily.

A dual combination of rosiglitazone/glimepiride is usually given indoses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosagestrengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).

A dual combination of pioglitazone/glimepiride is usually given in dosesfrom 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and45/4 mg).

A dual combination of rosiglitazone/metformin is usually given in dosesfrom 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500,2/500, 4/500, 2/1000 and 4/1000 mg).

A dual combination of pioglitazone/metformin is usually given in dosesfrom 15/500 once or twice daily to 15/850 mg thrice daily (typicaldosage strengths are 15/500 and 15/850 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

Acarbose is usually given in doses from 25 to 100 mg with meals (up to300 mg/day, typical dosage strengths are 25, 50 and 100 mg). Miglitol isusually given in doses from 25 to 100 mg with meals (up to 300 mg/day,typical dosage strengths are 25, 50 and 100 mg).

Conventional antidiabetics and antihyperglycemics typically used inmono- or dual or triple (add-on or initial) combination therapy mayinclude, without being limited to, metformin, sulphonylureas,thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 andGLP-1 analogues, as well as insulin and insulin analogues, such as e.g.those agents indicated herein by way of example, including combinationsthereof.

Examples of combination partners that lower the lipid level in the bloodare HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin,lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin;fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil,etofibrate and etofyllinclofibrate; nicotinic acid and the derivativesthereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists;inhibitors of acyl-coenzyme A:cholesterolacyltransferase (ACAT; EC2.3.1.26) such as avasimibe; cholesterol resorption inhibitors such asezetimib; substances that bind to bile acid, such as cholestyramine,colestipol and colesevelam; inhibitors of bile acid transport; HDLmodulating active substances such as D4F, reverse D4F, LXR modulatingactive substances and FXR modulating active substances; CETP inhibitorssuch as torcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO2007/005572 (anacetrapib); LDL receptor modulators; and ApoB100antisense RNA.

A dosage of atorvastatin is usually from 1 mg to 40 mg or 10 mg to 80 mgonce a day.

Examples of combination partners that lower blood pressure arebeta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol andcarvedilol; diuretics such as hydrochlorothiazide, chlortalidon,xipamide, furosemide, piretanide, torasemide, spironolactone,eplerenone, amiloride and triamterene; calcium channel blockers such asamlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine,felodipine, lacidipine, lercanipidine, manidipine, isradipine,nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such asramipril, lisinopril, cilazapril, quinapril, captopril, enalapril,benazepril, perindopril, fosinopril and trandolapril; as well asangiotensin II receptor blockers (ARBs) such as telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan andeprosartan.

A dosage of telmisartan is usually from 20 mg to 320 mg or 40 mg to 160mg per day.

Examples of combination partners which increase the HDL level in theblood are Cholesteryl Ester Transfer Protein (CETP) inhibitors;inhibitors of endothelial lipase; regulators of ABC1; LXRalphaantagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/betaregulators, and substances that increase the expression and/or plasmaconcentration of apolipoprotein A-I.

Examples of combination partners for the treatment of obesity aresibutramine; tetrahydrolipstatin (orlistat); alizyme; dexfenfluramine;axokine; cannabinoid receptor 1 antagonists such as the CB1 antagonistrimonobant; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 aswell as NPY2 antagonists; beta3-AR agonists such as SB-418790 andAD-9677; 5HT2c receptor agonists such as APD 356 (lorcaserin); myostatininhibitors; Acrp30 and adiponectin; steroyl CoA desaturase (SCD1)inhibitors; fatty acid synthase (FAS) inhibitors; CCK receptor agonists;Ghrelin receptor modulators; Pyy 3-36; orexin receptor antagonists; andtesofensine; as well as the dual combinations bupropion/naltrexone,bupropion/zonisamide, topiramate/phentermine andpramlintide/metreleptin.

Examples of combination partners for the treatment of atherosclerosisare phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mgto 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958,U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDLantibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1inhibitors.

Pharmaceutical Compositions, Formulations, Tablets Comprising SuchFormulations and Process for their Preparation According to thisInvention

The present invention refers to pharmaceutical compositions comprisingfixed dose combinations of a DPP-4 inhibitor drug and the partner drugmetformin, and processes for the preparation thereof.

In a more detailed aspect, the present invention refers to oral soliddosage forms for fixed dose combination (FDC) of a selected dipeptidylpeptidase-4 (DPP-4) inhibitor drug and the partner drug metformin. TheFDC formulations are chemically stable and either a) display similarityof in-vitro dissolution profiles and/or are bioequivalent to the freecombination, or b) allow to adjust the in-vitro and in-vivo performanceto desired levels. In a preferred embodiment the invention refers tochemically stable FDC formulations maintaining the original dissolutionprofiles of corresponding mono tablets of each individual entity, with areasonable tablet size.

The enzyme DPP-4 also known as CD26 is a serine protease known to leadto the cleavage of a dipeptide from the N-terminal end of a number ofproteins having at their N-terminal end a prolin or alanin residue. Dueto this property DPP-4 inhibitors interfere with the plasma level ofbioactive peptides including the peptide GLP-1 and are considered to bepromising drugs for the treatment of diabetes mellitus.

For example, DPP-4 inhibitors and their uses are disclosed in WO2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 orWO2007/014886; or in WO 2004/050658, WO 2004/111051, WO 2005/058901, WO2005/097798; WO 2006/068163, WO 2007/071738, WO 2008/017670; WO2007/128721, WO 2007/128724 or WO 2007/128761, or WO 2009/121945.

The biguanide antihyperglycemic agent metformin is disclosed in U.S.Pat. No. 3,174,901. The preparation of metformin (dimethyldiguanide) andits hydrochloride salt is state of the art and was disclosed first byEmil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794. Otherpharmaceutically acceptable salts of metformin can be found in U.S.application Ser. No. 09/262,526 filed Mar. 4, 1999 or U.S. Pat. No.3,174,901. It is preferred that the metformin employed herein be themetformin hydrochloride salt.

Unless specifically noted, in the present context the terms “DPP-4inhibitor(s)”, “biguanide(s)”, or any species thereof like “metformin”,are also intended to comprise any pharmaceutically acceptable saltthereof, crystal form, hydrate, solvate, diastereomer or enantiomerthereof.

For avoidance of any doubt, the disclosure of each of the foregoingdocuments cited above is specifically incorporated herein by referencein its entirety.

In attempts to prepare pharmaceutical compositions of selected DPP-4inhibitors it has been observed, that the DPP-4 inhibitors with aprimary or secondary amino group show incompatibilities, degradationproblems, or extraction problems with a number of customary excipientssuch as microcrystalline cellulose, sodium starch glycolate,croscarmellose sodium, tartaric acid, citric acid, glucose, fructose,saccharose, lactose, maltodextrines. Though the compounds themselves arevery stable, they react with incompatible partner drug, or its impurityproduct, and/or with many excipients used in solid dosage forms and withimpurities of excipients, especially in tight contact provided intablets and at high excipient/drug ratios. The amino group appears toreact with reducing sugars and with other reactive carbonyl groups andwith carboxylic acid functional groups formed for example at the surfaceof microcrystalline cellulose by oxidation. These unforeseendifficulties are primarily observed in low dosage ranges of the DPP-4inhibitor used, which are required due to their surprising potency,and/or high dosage ranges of the partner drug used. Thus, pharmaceuticalcompositions are required to solve these technical problems, which maybe associated with the unexpected potency of selected DPP-4 inhibitorcompounds.

Other aims of the present invention will become apparent to the skilledman from the foregoing and following remarks.

It has now been found that the pharmaceutical compositions, which aredescribed in greater details herein, have surprising and particularlyadvantageous properties.

In particular, it has been found that by the use of a nucleophilicand/or basic agent, which may be suitable for stabilizing, such as e.g.a suitable buffering agent as stabilizer, within these pharmaceuticalcompositions one can overcome these problems, e.g. of incompatibilityand poor stability, especially decomposition and/or “assay decrease”which may be caused e.g. by reaction (e.g. by acylation, urea formationor Maillard reaction, or the like) of free base type DPP-4 inhibitorswhen combined with an incompatible partner drug, or its impurity productand/or a pharmaceutical excipient having such functional group (such asa reducing end of a sugar or an acyl group, such as e.g. an acetyl orcarbamoyl group) to form derivatives with the free base type DPP-4inhibitors, such as e.g. N-acetyl or N-carbamoyl derivatives. Therefore,by the use of a suitable nucleophilic and/or basic agent (e.g. abuffering and/or pH modifying agent) within these pharmaceuticalcompositions protection against decomposition and degradation can beachieved.

Thus, the present invention is directed to a chemically stable FDCformulation comprising a DPP-4 inhibitor, a partner drug, and anucleophilic and/or basic agent.

Thus, the present invention is also directed to a chemically stable FDCformulation comprising a DPP-4 inhibitor, a partner drug, and a suitablebuffering agent.

Thus, the present invention is also directed to a chemically stable FDCformulation comprising a DPP-4 inhibitor, a partner drug, and a pHmodifying agent.

A DPP-4 inhibitor within the meaning of the present invention includes,without being limited to, any of those DPP-4 inhibitors mentionedhereinabove and hereinbelow, preferably orally active DPP-4 inhibitors.

In a closer embodiment, a DPP-4 inhibitor within the meaning of thepresent invention includes a DPP-4 inhibitor with an amino group,especially a free or primary amino group.

In a yet closer embodiment, a DPP-4 inhibitor in the context of thepresent invention is a DPP-4 inhibitor with a primary amino group,particularly with a free primary amino group.

The partner drug used is metformin, particularly metformin hydrochloride(1,1-dimethylbiguanide hydrochloride or metformin HCl).

The buffering agent used may be a basic amino acid, which has anintramolecular amino group and alkaline characteristics (isoelectricpoint, pl: 7.59-10.76), such as e.g. L-arginine, L-lysine orL-histigine. A preferred buffering agent within the meaning of thisinvention is L-arginine. L-Arginine has a particular suitablestabilizing effect on the compositions of this invention, e.g. bysuppressing degradation of the DPP-4 inhibitor in the presence of thepartner drug.

The present invention is directed to a pharmaceutical comprising a DPP-4inhibitor, a partner drug, a nucleophilic and/or basic agent, and one ormore pharmaceutical excipients.

The present invention is also directed to a pharmaceutical compositioncomprising a DPP-4 inhibitor, a partner drug, a suitable bufferingagent, and one or more pharmaceutical excipients.

The present invention is also directed to a pharmaceutical comprising aDPP-4 inhibitor, a partner drug, a pH modifying agent, and one or morepharmaceutical excipients.

In an embodiment, the present invention is directed to a pharmaceuticalcomposition (e.g. an oral solid dosage form, particularly a tablet)comprising a DPP-4 inhibitor; a partner drug (particularly metformin);and L-arginine for stabilizing the composition and/or the DPP-4inhibitor, particularly against chemical degradation; as well as one ormore pharmaceutical excipients.

In another embodiment, the present invention is directed to apharmaceutical composition (e.g. an oral solid dosage form, particularlya tablet) obtainable from a DPP-4 inhibitor; a partner drug(particularly metformin); and L-arginine for stabilizing the compositionand/or the DPP-4 inhibitor, particularly against chemical degradation;as well as one or more pharmaceutical excipients.

In general, pharmaceutical excipients which may be used may be selectedfrom the group consisting of one or more fillers, one or more binders ordiluents, one or more lubricants, one or more disintegrants, and one ormore glidants, one or more film-coating agents, one or moreplasticizers, one or more pigments, and the like.

The pharmaceutical compositions (tablets) of this invention compriseusually a binder.

In more detail, the pharmaceutical compositions (tablets) of thisinvention comprise usually one or more fillers (e.g. D-mannitol, cornstarch and/or pregelatinized starch), a binder (e.g. copovidone), alubricant (e.g. magnesium stearate), and a glidant (e.g. colloidalanhydrous silica).

Suitably the pharmaceutical excipients used within this invention areconventional materials such as D-mannitol, corn starch, pregelatinizedstarch as a filler, copovidone as a binder, magnesium stearate as alubricant, colloidal anhydrous silica as a glidant, hypromellose as afilm-coating agent, propylene glycol as a plasticizer, titanium dioxide,iron oxide red/yellow as a pigment, and talc, etc.

A typical composition according to the present invention comprises thebinder copovidone (also known as copolyvidone or Kollidon VA64).

Further, a typical composition according to the present inventioncomprises the filler corn starch, the binder copovidone, the lubricantmagnesium stearate, and the glidant colloidal anhydrous silica.

A pharmaceutical composition according to an embodiment of the presentinvention is intended for the treatment of diabetes and/or to achieveglycemic control in a type 1 or type 2 diabetes mellitus patient andcomprises a fixed dose combination formulation as described hereintogether with suitable pharmaceutical excipients. Additionally thecompositions can be used to treat rheumatoid arthritis, obesity andosteoporosis as well as to support allograft transplantation.

Thus, in particular, the present invention is directed to apharmaceutical composition (especially an oral solid dosage form,particularly a tablet) comprising a DPP-4 inhibitor, metforminhydrochloride, L-arginine and one or more pharmaceutical excipients,particularly one or more fillers, one or more binders, one or moreglidants, and/or one or more lubricants.

In more particular, the present invention is directed to apharmaceutical composition (especially an oral solid dosage form,particularly a tablet) comprising a DPP-4 inhibitor, metforminhydrochloride, L-arginine, copovidone as binder and one or more furtherpharmaceutical excipients.

Typical pharmaceutical compositions of this invention may comprise inthe DPP-4 inhibitor portion 0.1-10 L-arginine (such as e.g. about 0.1%,0.25%, 0.556%, 2.12%, 2.22% or 10%) by weight of total DPP-4 inhibitorportion, particularly about 2% (e.g. more specifically, 2.12% by weightof total tablet core of uncoated monolayer tablet).

Typical pharmaceutical compositions of this invention may comprise inthe DPP-4 inhibitor portion (% by weight of total DPP-4 inhibitorportion):

0.2-10% DPP-4 inhibitor, and

0.1-10 L-arginine.

Typical pharmaceutical compositions of this invention may comprise theDPP-4 inhibitor and L-arginine in a weight ratio of from about 1:20 toabout 10:1 or from about 1:15 to about 10:1 or from about 1:10 to about10:1, especially from 1:10 to 5:2, such as e.g. in a weight ratio of1:10, 1:8.5, 1:5, 1:1, or 1:0.4, more detailed in a weight ratio of 2.5mg:25 mg, 2.5 mg:21.2 mg, 2.5 mg:12.5 mg, 2.5 mg:2.5 mg, or 2.5 mg:1 mg.

Typical pharmaceutical compositions of this invention may comprisemetformin hydrochloride and L-arginine in a weight ratio of from about40:1 to about 1000:1, such as e.g. in a weight ratio of 40:1, 200:1,340:1, 400:1, 500:1, 850:1, or 1000:1, more detailed in a weight ratioof 500 mg:12.5 mg, 850 mg:21.2 mg, 1000 mg:25 mg, 500 mg:2.5 mg, 850mg:2.5 mg, 1000 mg:2.5 mg, 500 mg:1 mg, 850 mg:1 mg, or 1000 mg:1 mg.

Typical pharmaceutical compositions of this invention may comprise theDPP4-inhibitor, metformin hydrochloride and L-arginine in a weight ratioof from about 1:200:0.4 to about 1:200:5 (e.g. 1:200:0.4, 1:200:1,1:200:5), or from about 1:340:0.4 to about 1:340:8.5 (e.g. 1:340:0.4,1:340:1, 1:340:8.5), or from about 1:400:0.4 to about 1:400:10 (e.g.1:400:0.4, 1:400:1, 1:400:10).

Typical pharmaceutical compositions of this invention may comprise oneor more of the following amounts (% by weight of total coated tabletmass):

0.1-0.5% DPP-4 inhibitor,47-85% metformin HCl,

0.07-2.2% L-arginine,

3.9-8.1% binder (e.g. copovidone),2.3-5.9% filler 1 (e.g. corn starch),0-4.4% filler 2 (e.g. pregelatinized starch),0-33% filler 3 (e.g. D-mannitol),0.7-1.5% lubricant (e.g. magnesium stearate), and0.1-0.5% glidant (e.g. colloidal anhydrous silica).

Further details about the FDC formulations of this invention, e.g. theingredients, ratio of ingredients (such as e.g. ratio of DPP-4inhibitor, metformin hydrochloride, L-arginine and/or excipients),particularly with respect to special dosage forms (tablets) used withinthis invention as well as their preparation, become apparent to theskilled person from the disclosure hereinbefore and hereinafter(including by way of example the following examples as well as theclaims).

In a first embodiment (embodiment A), a DPP-4 inhibitor in the contextof the present invention is any DPP-4 inhibitor of

wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl,(4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl,(3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl,(4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyland R2 denotes 3-(R)-amino-piperidin-1-yl,(2-amino-2-methyl-propyl)-methylamino or(2-(S)-amino-propyl)-methylamino, or its pharmaceutically acceptablesalt;

In a second embodiment (embodiment B), a DPP-4 inhibitor in the contextof the present invention is a DPP-4 inhibitor selected from the groupconsisting of

sitagliptin, vildagliptin, saxagliptin and alogliptin,or its pharmaceutically acceptable salt.

Regarding the first embodiment (embodiment A), preferred DPP-4inhibitors are any or all of the following compounds and theirpharmaceutically acceptable salts:

-   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(142):

-   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(252)):

-   1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(80)):

-   2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one    (compare WO 2004/050658, example 136):

-   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyin-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine    (compare WO 2006/029769, example 2(1)):

-   1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(30)):

-   1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(39)):

-   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine    (compare WO 2006/029769, example 2(4)):

-   1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(52)):

-   1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(81)):

-   1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(82)):

-   1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(83)):

These DPP-4 inhibitors are distinguished from structurally comparableDPP-4 inhibitors, as they combine exceptional potency and a long-lastingeffect with favourable pharmacological properties, receptor selectivityand a favourable side-effect profile or bring about unexpectedtherapeutic advantages or improvements when combined with otherpharmaceutical active substances. Their preparation is disclosed in thepublications mentioned.

A more preferred DPP-4 inhibitor among the abovementioned DPP-4inhibitors of embodiment A of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,particularly the free base thereof (which is also known as BI 1356).

Regarding the second embodiment (embodiment B), preferred DPP-4inhibitors are selected from the group consisting of vildagliptin,saxagliptin and alogliptin, and their pharmaceutically acceptable salts.

Unless otherwise noted, according to this invention it is to beunderstood that the definitions of the above listed DPP-4 inhibitorsalso comprise their pharmaceutically acceptable salts as well ashydrates, solvates and polymorphic forms thereof. With respect to salts,hydrates and polymorphic forms thereof, particular reference is made tothose which are referred to hereinabove and hereinbelow.

With respect to embodiment A, the methods of synthesis for the DPP-4inhibitors according to embodiment A of this invention are known to theskilled person. Advantageously, the DPP-4 inhibitors according toembodiment A of this invention can be prepared using synthetic methodsas described in the literature. Thus, for example, purine derivatives offormula (I) can be obtained as described in WO 2002/068420, WO2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, thedisclosures of which are incorporated herein. Purine derivatives offormula (II) can be obtained as described, for example, in WO2004/050658 or WO 2005/110999, the disclosures of which are incorporatedherein. Purine derivatives of formula (III) can be obtained asdescribed, for example, in WO 2006/068163, WO 2007/071738 or WO2008/017670, the disclosures of which are incorporated herein. Thepreparation of those DPP-4 inhibitors, which are specifically mentionedhereinabove, is disclosed in the publications mentioned in connectiontherewith. Polymorphous crystal modifications and formulations ofparticular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO2007/128724, respectively, the disclosures of which are incorporatedherein in their entireties.

With respect to embodiment B, the methods of synthesis for the DPP-4inhibitors of embodiment B are described in the scientific literatureand/or in published patent documents, particularly in those citedherein.

With respect to the first embodiment (embodiment A), the dosagetypically required of the DPP-4 inhibitors mentioned herein inembodiment A when administered orally is 0.5 mg to 100 mg, preferably2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1mg to 5 mg, in each case 1 to 4 times a day. Thus, the dosage requiredof1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinewhen administered orally is 0.5 mg to 10 mg per patient per day,preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.

A dosage form prepared with a pharmaceutical composition comprising aDPP-4 inhibitor mentioned herein in embodiment A contain the activeingredient in a dosage range of 0.1-100 mg, in particular 0.5 to 10 mg.Thus, particular dosage strengths of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineare 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg. A more particular unit dosagestrength of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefor inclusion into fixed dose combination pharmaceutical compositions ofthe present invention is 2.5 mg.

With respect to the second embodiment (embodiment B), the doses of DPP-4inhibitors mentioned herein in embodiment B to be administered tomammals, for example human beings, of, for example, approximately 70 kgbody weight, may be generally from about 0.5 mg to about 350 mg, forexample from about 10 mg to about 250 mg, preferably 20-200 mg, morepreferably 20-100 mg, of the active moiety per person per day, or fromabout 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day,divided preferably into 1 to 4 single doses which may, for example, beof the same size. Single dosage strengths comprise, for example, 2.5, 5,10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor activemoiety.

A dosage strength of the DPP-4 inhibitor sitagliptin is usually between25 and 200 mg of the active moiety. A recommended dose of sitagliptin is100 mg calculated for the active moiety (free base anhydrate) oncedaily. Unit dosage strengths of sitagliptin free base anhydrate (activemoiety) are 25, 50, 75, 100, 150 and 200 mg. Particular unit dosagestrengths of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg. Anequivalent amount of sitagliptin phosphate monohydrate to thesitagliptin free base anhydrate is used in the pharmaceuticalcompositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg,respectively. Adjusted dosages of 25 and 50 mg sitagliptin are used forpatients with renal failure.

A dosage range of the DPP-4 inhibitor vildagliptin is usually between 10and 150 mg daily, in particular between 25 and 150 mg, 25 and 100 mg or25 and 50 mg or 50 and 100 mg daily. Particular examples of daily oraldosage are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a moreparticular aspect, the daily administration of vildagliptin is between25 and 150 mg or between 50 and 100 mg. In another more particularaspect, the daily administration of vildagliptin is 50 or 100 mg. Theapplication of the active ingredient may occur up to three times a day,preferably one or two times a day. Particular dosage strengths are 50 mgor 100 mg vildagliptin.

Metformin is usually given in doses varying from about 250 mg to 3000mg, particularly from 500 mg to 2000 mg up to 2500 mg per day usingvarious dosage regimens.

A dosage range of the partner drug metformin is usually from 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or from 300 mg to 1000 mgonce or twice a day.

The unit dosage strengths of the metformin hydrochloride for use in thepresent invention may be from 100 mg to 2000 mg or from 250 mg to 2000mg, preferably from 250 mg to 1000 mg. Particular dosage strengths maybe 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride. Theseunit dosage strengths of metformin hydrochloride represent the dosagestrengths approved in the US for marketing to treat type 2 diabetes.More particular unit dosage strengths of metformin hydrochloride forincorporation into the fixed dose combination pharmaceuticalcompositions of the present invention are 500, 850 and 1000 mg ofmetformin hydrochloride.

The amount of the DPP-4 inhibitor and of the partner drug in thepharmaceutical composition according to this invention correspond to therespective dosage ranges as provided hereinbefore. For example, apharmaceutical composition comprises1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinein an amount of 0.5 mg to 10 mg (namely 0.5 mg, 1 mg, 2.5 mg, 5 mg or 10mg) and of metformin hydrochloride in an amount of 250 mg to 1000 mg(namely 250, 500, 625, 750, 850 or 1000 mg).

Specific embodiments of dosage strengths for1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand metformin hydrochloride in the fixed dose combinations of thepresent invention are the following:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, and 500 mg metformin hydrochloride;(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, and 850 mg metformin hydrochloride;(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, and 1000 mg metformin hydrochloride.

The particular fixed dose combinations of BI 1356 and metformin of thepresent invention may be administered once or twice daily to thepatient, in particular twice daily.

In a preferred aspect of the present invention, the present invention isdirected to a pharmaceutical composition (especially an oral soliddosage form, particularly a tablet) comprising or obtainable from

a DPP-4 inhibitor selected from the group consisting of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, vildagliptin, saxagliptin and alogliptin,metformin hydrochloride,

L-arginine,

and one or more pharmaceutical excipients, such as e.g. those describedherein.

A particularly preferred DPP-4 inhibitor to be emphasized within themeaning of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base (also known as BI 1356).

In particular, it has been found that L-arginine is effective asstabilizing agent for FDC combinations of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base with metformin HCl. Even after 6 months storage at acceleratedconditions L-arginine is able to suppress degradation of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base effectively. The effect seems to be concentration dependent.Thus, L-arginine may act as stabilizing and buffering agent in theformulation.

In a more preferred aspect of the present invention, the presentinvention is directed to a pharmaceutical composition (especially anoral solid dosage form, particularly a tablet) comprising or made from

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base (BI 1356),metformin hydrochloride,

L-arginine,

and one or more pharmaceutical excipients, such as e.g. those describedherein.

Typical pharmaceutical compositions according to this invention compriseor are made by comprising combining any one of the following amounts(1), (2) or (3) of active ingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and from 1.0 mg to 12.5 mgL-arginine (specifically 1.0 mg, 2.5 mg or 12.5 mg L-arginine);(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and from 1.0 mg to 21.2 mgL-arginine (specifically 1.0 mg, 2.5 mg or 21.2 mg L-arginine);(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and from 1.0 mg to 25.0 mgL-arginine (specifically 1.0 mg, 2.5 mg or 25 mg L-arginine).

In a further aspect of the present invention, the present inventionprovides methods of manufacturing of the compositions, formulations,blends or dosage forms of this invention, such as e.g. by using methodsknown to one skilled in the art and/or in a manner as described herein,for example they may be obtained by processes comprising using (e.g.mixing, combining, blending and/or composing) the components and/oringredients, or pre-mixtures thereof, mentioned hereinbefore andhereinafter, as well as the present invention further providescompositions, formulations, blends or dosage forms obtainable by thesemethods or processes and/or obtainable from the components, ingredients,pre-mixtures and/or mixtures mentioned hereinbefore and hereinafter.

In a further aspect of the present invention, the present inventionprovides a pharmaceutical composition, formulation, blend or dosage formof this invention which is substantially free of or only marginallycomprises impurities and/or degradation products; that means, forexample, that the composition, formulation, blend or dosage fromincludes about <5%, or about <4%, or about <3%, or less than about 2%,preferably less than about 1%, more preferably less than about 0.5%,even more preferably less than about 0.2% of any individual or totalimpurity or degradation product(s) by total weight, such as e.g.N-acetyl, N-formyl, N-methyl and/or N-carbamoyl derivative of the freebase type DPP-4 inhibitor. The content and/or degradation can bedetermined by well-known analytical methods, for example using HPLCmethods.

In this context, in a further aspect of the present invention, thepresent invention provides derivatives of a DPP-4 inhibitor having anamino group, particularly a free primary amino group, as mentionedherein, said derivatives being obtainable by acetylation of the aminogroup (e.g. to yield the group —NHC(O)CH₃) or by carbamoylation of theamino group (e.g. to yield the group —NHC(O)NH₂) or by formylation ofthe amino group (e.g. to yield the group —NHC(O)H) or by methylation ofthe amino group (e.g. to yield the group —NHCH₃). Compositions,formulations and dosage forms such as described herein comprising one ormore of such derivatives (e.g. in trace amounts and mixed with therespective DPP-4 inhibitors indicated herein) or substantially freethereof are also contemplated.

Dosage Forms for the FDC Formulations of this Invention:

Another purpose of this invention is to develop the FDC formulations ofthis invention with a reasonable tablet size, with good tabletproperties (e.g. stability, hardness, friability, disintegration,content uniformity and the like) and, in a preferred embodiment, withoutdisturbing the original dissolution profiles of each mono tablet in caseof desired proof of bioequivalence with minimized risk of failure.

Designing of the dosage form is an important matter not only to optimizethe tablet size and dissolution profiles but also to minimize the amountof stabilizing agent, because the pH change by dissolving of bufferingagent may affect the dissolution profiles of the DPP-4 inhibitor or apartner drug. The selection of the dosage form is depending on the dosestrengths of the active ingredients used and their physicochemical andsolid state characteristics.

A conventional approach (i.e. physical separation) may not be useful forstabilization of certain DPP-4 inhibitors of this invention. A bufferingagent like L-arginine need to be added into the formulation forsuppressing degradation, however it may be necessary to minimize theamount of L-arginine because its alkaline characteristics give anegative impact on the dissolution profiles or the stability of theDPP-4 inhibitor or a partner drug.

Thus, it has been found that suitable dosage forms for the FDCformulations of this invention are film-coated tablets (film-coating fordrug loading, such as particularly DPP-4 inhibitor drug loading by filmcoating on tablet cores containing the partner drug), mono-layertablets, bi-layer tablets, tri-layer tablets and press-coated tablets(e.g. tablet-in-tablet or bull's eye tablet with DPP-4 inhibitor core),which dosage forms are good measures to achieve the goal underconsideration of desired pharmaceutical profiles and characteristics ofa DPP-4 inhibitor and a partner drug used.

Said dosage forms have been found to be applicable to the FDCformulations either keeping the original dissolution profiles of eachmono tablet or adjusting the profiles to desired levels, e.g. includingextended release characteristics, and a reasonable tablet size.

A typical mono-layer tablet of this invention comprises a DPP-4inhibitor, metformin hydrochloride, L-arginine, one or more fillers(such as e.g. corn starch), one or more binders (such as e.g.copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate).

In a preferred embodiment of the present invention, the presentinvention is directed to an oral solid pharmaceutical composition,preferably a tablet, particularly a mono-layer tablet comprising or madefrom

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(also known as BI 1356, e.g. in an amount of 2.5 mg),metformin (particularly metformin hydrochloride, e.g. in an amount of500 mg, 850 mg or 1000 mg),

L-arginine,

and one or more pharmaceutical excipients, particularly one or morefillers (e.g. corn starch), one or more binders (e.g. copovidone), oneor more glidants (e.g. colloidal anhydrous silica) and/or one or morelubricants (e.g. magnesium stearate),as well as, optionally, a film coat e.g. comprising one or morefilm-coating agents (e.g. hypromellose), one or more plasticizers (e.g.propylene glycol), one or more pigments (e.g. titanium dioxide, ironoxide red and/or iron oxide yellow) and/or one or more glidants (e.g.talc).

A method of manufacturing a tablet of this invention comprisestabletting (e.g. compression) of one or more final blends in form ofgranules. Granules of the (final) blend(s) according to this inventionmay be prepared by methods well-known to one skilled in the art (e.g.high shear wet granulation or fluid bed granulation). Granules accordingto this invention as well as details of granulation processes (includingtheir separate steps) for the preparation of granules of this inventionare described by way of example in the following examples.

An illustrative granulation process for the preparation of granulescomprising the mono-layer composition comprises

i.) combining (e.g. dissolving or dispersing) L-arginine, a binder (e.g.copovidone) and, optionally, the DPP-4 inhibitor (e.g. BI 1356) in asolvent or mixture of solvents such as purified water at ambienttemperature to produce a granulation liquid;ii.) blending metformin HCl, a filler (e.g. corn starch) and,optionally, the DPP-4 inhibitor (e.g. BI 1356) in a suitable mixer (e.g.fluid-bed granulator) to produce a pre-mix; wherein the DPP-4 inhibitor(e.g. BI 1356) may be included either in the granulation liquid obtainedin i.) or in the pre-mix obtained in ii.), preferably BI 1356 isdispersed in the granulation liquid and is absent in the pre-mix;iii.) spraying the granulation-liquid into the pre-mix and granulatingthe mixture for example in a fluid-bed granulator, preferably under drycondition;iv.) drying the granulate, e.g. at about 70° C. inlet air temperatureuntil the desired loss on drying value in the range of 1-2% is obtained;v.) delumping the dried granulate for example by sieving through a sievewith a mesh size of 0.5 to 1.0 mm;vi.) blending the sieved granulate and preferably sieved glidant (e.g.colloidal anhydrous silica) in a suitable blender;vii.) adding preferably sieved lubricant (e.g. magnesium stearate) tothe granulate for final blending for example in the free-fall blender.

Preferentially, a mono-layer tablet according to this inventioncomprises or is obtainable from a mixture comprising any one of thefollowing amounts (1), (2) or (3) of active ingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and 12.5 mg L-arginine;(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and 21.2 mg L-arginine;(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and 25 mg L-arginine.

A typical bi-layer tablet of this invention comprises

a DPP-4 inhibitor portion comprising a DPP-4 inhibitor, L-arginine, oneor more fillers (such as e.g. D-mannitol, pregelatinized starch and cornstarch), one or more binders (such as e.g. copovidone) and one or morelubricants (such as e.g. magnesium stearate), anda metformin HCl portion comprising metformin hydrochloride, one or morefillers (such as e.g. corn starch), one or more binders (such as e.g.copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate).

Preferentially, a bi-layer tablet according to this invention comprisesor is obtainable from a mixture comprising any one of the followingamounts (1), (2) or (3) of active ingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and 2.5 mg L-arginine;(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and 2.5 mg L-arginine;(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and 2.5 mg L-arginine.

A typical press-coated tablet (tablet-in-tablet or bull's eye tablet) ofthis invention comprises a DPP-4 inhibitor core portion comprising aDPP-4 inhibitor, L-arginine, one or more fillers (such as e.g.D-mannitol, pregelatinized starch and corn starch), one or more binders(such as e.g. copovidone) and one or more lubricants (such as e.g.magnesium stearate), and

a metformin HCl portion comprising metformin hydrochloride, one or morefillers (such as e.g. corn starch), one or more binders (such as e.g.copovidone), one or more glidants (such as e.g. colloidal anhydroussilica) and one or more lubricants (such as e.g. magnesium stearate).

Preferentially, a press-coated tablet (tablet-in-tablet or bull's eyetablet) according to this invention comprises or is obtainable from amixture comprising any one of the following amounts (1), (2) or (3) ofactive ingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and 1.0 mg L-arginine;(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and 1.0 mg L-arginine;(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and 1.0 mg L-arginine.

A typical film-coated tablet (DPP-4 inhibitor coating on metformin HCltablet, i.e. drug layering by film-coating for drug loading) of thisinvention comprises a metformin HCl core portion comprising metforminhydrochloride, one or more fillers (such as e.g. corn starch), one ormore binders (such as e.g. copovidone), one or more glidants (such ase.g. colloidal anhydrous silica) and one or more lubricants (such ase.g. magnesium stearate),

wherein said core portion is seal-coated with a film coat comprising oneor more film-coating agents (such as e.g. hypromellose), one or moreplasticizers (such as e.g. propylene glycol), one or more pigments (suchas e.g. titanium dioxide, iron oxide red and/or iron oxide yellow) andone or more glidants (such as e.g. talc); anda DPP-4 inhibitor layer comprising a DPP-4 inhibitor, L-arginine, one ormore film-coating agents (such as e.g. hypromellose) and one or moreplasticizers (such as e.g. propylene glycol).

Preferentially, a film-coated tablet (DPP4-inhibitor drug loading)according to this invention comprises or is obtainable from a mixturecomprising any one of the following amounts (1), (2) or (3) of activeingredients and L-arginine:

(1) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 500 mg metformin hydrochloride, and 2.5 mg L-arginine;(2) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 850 mg metformin hydrochloride, and 2.5 mg L-arginine;(3) 2.5 mg of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base, 1000 mg metformin hydrochloride, and 2.5 mg L-arginine.

Preferably, these abovementioned tablets (mono-, bi-layer, press-coatedand drug-coated tablets) are further over-coated with a final film coat,which comprises a film-coating agent (such as e.g. hypromellose), aplasticizer (such as e.g. propylene glycol), pigments (such as e.g.titanium dioxide, iron oxide red and/or iron oxide yellow) and a glidant(such as e.g. talc). Typically this additional film over-coat mayrepresent 1-4%, preferentially 1-2%, of the total mass of thecomposition.

The following dosage forms of the invention can be applied to the FDCformulation of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinefree base (BI 1356) and metformin hydrochloride based on thecharacteristics of drug substances and requirements of the desiredpharmaceutical profiles:

a) Mono-Layer Tablets

Mono-layer tablets with L-arginine show satisfactory stability results,good dissolution properties and good content uniformity (CU). Mono-layertablets can be manufactured using conventional technologies (includingfluid-bed granulation for the DPP-4 inhibitor and metforminhydrochloride, e.g. comprising adding the DPP-4 inhibitor as powder oras an aqueous suspension in the granulation liquid to the fluid bedgranulator).

b) Bi-Layer Tablets

Bi-layer tablets with L-arginine show promising stability results, gooddissolution properties and good CU. Bi-layer tablets can be manufacturedusing conventional bi-layer tableting technologies (e.g. rotary bi-layertableting machine).

c) Press-Coated Tablets

Press-coated tablets (tablet-in-tablets and advanced press-coated bull'seye tablets) show promising stability, good CU and dissolution.Press-coated tablets can be manufactured using conventionalpress-coating technology, such as e.g. on a Kilian tablet press toobtain tablet-in-tablet or on other conventional press-coater to obtainbull's eye tablet. As an advantage of this approach, it is easy tominimize the amount of L-arginine in the formulation and control theassay and CU of the DPP-4 inhibitor portion (very small amount of drugloading; 2.5 mg/tablet where the dose strengths of metformin HCl are500, 850 and 1000 mg/tablet). Another advantage is that DPP-4inhibitor—and metformin HCl—portion can be designed flexibly to minimizethe tablet size. A modified press-coated tablet named “bull's eyetablet” may be a universal dosage potentially for bi-layer tablets aswell as other FDC. Bull's eye tablet can be manufactured in a one-steppress-coating without separate core formation (like in bi-layertableting) being necessary.

It is to be noted that within the meaning of this invention the skilledperson is aware about what is meant with the phrase “bull's eye tablet”used herein. As it known to the skilled person, this tablet (alsoreferred to as an inlay tablet or a dot) is composed of an outer coatand an inner core, and in which, instead of the inner core zone beingcompletely surrounded by the outer coat, one surface of the zonecorresponding to the inner core zone is exposed.

d) Film-Coated Tablets (Drug Layering by Film-Coating for Drug Loading)

Coating of DPP-4 inhibitor drug substance on the metformin HCl tabletsshows acceptable dissolution results and promising stability data.L-arginine needs to be added into film-coating for stabilization. As anadvantage for this approach, it is possible to integrate DPP-4 inhibitorportion into a partner drug portion as it is, even if the dosage form isa modified/controlled release formulation. Within the film-coatingprocess coating endpoint determination is necessary via analytics.

The method of layering of the DPP-4 inhibitor by film-coating asdescribed herein (including the steps of seal-coating, drug-loading and,optional, over-coating) may be applied to any kind of cores or tabletswhich may comprise an active ingredient (e.g. a partner drug asmentioned herein), for example metformin cores or tablets, such as e.g.immediate release metformin tablets, sustained release metformintablets, extended release metformin tablets, modified release metformintablets, controlled release metformin tablets or delayed releasemetformin tablets. Thus, the present invention further relates to atablet which comprises a film-coat layer comprising the DPP-4 inhibitor,a film-forming agent (e.g. hypromellose), a plasticizer (e.g. propyleneglycol) and L-arginine, or which is obtainable by comprising using sucha method of layering of the DPP-4 inhibitor by film-coating as describedherein. The present invention also relates to a FDC tablet comprising animmediate or extended release metformin tablet core, a seal coat, afilm-coat layer comprising the DPP-4 inhibitor, and, optionally, anover-coat; e.g. each as described herein, as well as to such a FDCtablet made by a process comprising the following steps of seal-coatingon a metformin tablet core, layering of a DPP-4 inhibitor byfilm-coating and, optional, over-coating, e.g. each step such asdescribed herein.

Pharmaceutical immediate release dosage forms of this inventionpreferably have dissolution properties such that after 45 minutes foreach of the active ingredients at least 75%, even more preferably atleast 90% by weight of the respective active ingredient is dissolved. Ina particular embodiment, after 30 minutes for each of the activeingredients especially of the mono-layer tablet according to thisinvention (including tablet core and film-coated tablet) at least 70-75%(preferably at least 80%) by weight of the respective active ingredientis dissolved. In a further embodiment, after 15 minutes for each of theactive ingredients especially of the mono-layer tablet according to thisinvention (including tablet core and film-coated tablet) at least 55-60%by weight of the respective active ingredient is dissolved. Thedissolution properties can be determined in standard dissolution tests,e.g. according to standard pharmacopeias (e.g. using paddle method withagitation speed of 50 rpm, 0.1 M hydrochloric acid as dissolution mediumat a temperature of 37° C., and HPLC (BI 1356) and UV (metformin)analysis of the samples).

In the pharmaceutical compositions and pharmaceutical dosage formsaccording to the invention BI 1356, for example a crystalline formthereof, preferably has a particle size distribution (preferably byvolume) such that at least 90% of the respective active pharmaceuticalingredient has a particle size smaller than 200 μm, i.e. X90<200 μm,more preferably X90≦150 μm. More preferably the particle sizedistribution is such that X90≦100 μm, even more preferably X90≦75 μm. Inaddition the particle size distribution is preferably such that X90>0.1μm, more preferably X90≧1 μm, most preferably X90≧5 μm. Thereforepreferred particle size distributions are such that 0.1 μm<X90<200 μm,particularly 0.1 μm<X90≦150 μm, more preferably 1 μm≦X90≦150 μm, evenmore preferably 5 μm≦X90≦100 μm. A preferred example of a particle sizedistribution of BI 1356 is such that X90≦50 μm or 10 μm≦X90≦50 μm. Itcan be found that a pharmaceutical composition comprising BI 1356 with aparticle size distribution as indicated hereinbefore shows desiredproperties (e.g. with regard to dissolution, content uniformity,production, or the like). The indicated particle size properties aredetermined by laser-diffraction method, in particular low angle laserlight scattering, i.e. Fraunhofer diffraction. Alternatively, theparticle size properties can be also determined by microscopy (e.g.electron microscopy or scanning electron microscopy). The results of theparticle size distribution determined by different techniques can becorrelated with one another.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES 1. Mono-Layer Tablet

The composition of mono-layer tablets for a DPP-4 inhibitor of thisinvention (BI 1356)+metformin HCl FDC (Film-coated Tablets) is shown inTable 1.

TABLE 1 Composition of BI 1356 + Metformin HCl FDC Mono-layer TabletsDose Strength (BI 1356/metformin HCl), mg 2.5/500 2.5/850 2.5/1000Ingredient [mg] [%] [mg] [%] [mg] [%] BI 1356 2.50 0.42 2.50 0.25 2.500.21 Metformin Hydrochloride 500.0   84.75 850.00  85.00 1000.00   84.75L-Arginine 12.50  2.12 21.20  2.12 25.00  2.12 Corn starch 20.00  3.3933.10  3.31 42.50  3.60 Copovidone 47.50  8.05 80.50  8.05 95.00  8.05Colloidal Anhydrous Silica 2.50 0.42 4.20 0.42 5.00 0.42 Magnesiumstearate 5.00 0.85 8.50 0.85 10.00  0.85 Purified water* 186**   315**  372**   Total Mass (tablet core) 590.00  100.00 1000.00   100.001180.00   100.00 Hypromellose (5 mPa * s) 6.00 50.00 8.00 50.00 9.0050.00 Propylene glycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc 2.88 18.502.96 18.50  4.455 18.50 Titanium dioxide 2.40 25.00 4.00 25.00 3.6025.00 Iron oxide, yellow 0.12 1.25 0.20 1.25 Iron oxide, red 0.04 0.25 0.045 1.25 Purified water** 88**   117**   132**   Total Mass(film-coat) 12.00  100.00 16.00  100.00 18.00  100.00 Total Mass (coatedtablet) 602.00  1016.00   1198.00   **Removed during processing, doesnot appear in final product

Manufacturing Procedure (Mono-Layer Tablets):

DPP-4 inhibitor of this invention (e.g. BI 1356)+metformin HCl FDCmono-layer tablets are produced by a fluid-bed granulation process and aconventional tableting process with a rotary press. Optionally,metformin HCl and corn starch may be pre-treated by heating in a chamberof fluid-bed granulator to remove excessive HCl and/or impurity productsbefore mixing with the active DPP-4 inhibitor ingredient. After theoptional pre-treatment of metformin HCl and corn starch, the DPP-4inhibitor is either added as powder and premixed before fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64), L-arginine and purified water, or directlydispersed in the “granulation liquid”. After finishing of fluid-bedgranulation, the granulate is sieved with a suitable screen. The sievedgranulate is blended with colloidal anhydrous silica (Aerosil 200) andmagnesium stearate as a lubricant. The final mixture is compressed intotablets using a conventional rotary tablet press.

The tablet cores may be film-coated by an aqueous film-coatingsuspension, containing hypromellose as film-forming agent, propyleneglycol as plasticizer, talc as glidant and the pigments yellow ironoxide and/or red iron oxide and titanium dioxide.

Narrative more specific description of the preferred manufacturingprocess for the mono-layer tablets:

a) Metformin HCl and corn starch are sieved using a screen with a meshsize of 0.5 to1 mm before dispensing.b) L-arginine, BI 1356 and finally copolyvidon are dissolved resp.dispersed in purified water at ambient temperature with a propellermixer to produce the “Granulation Liquid”.c) Metformin HCl and corn starch are sucked into a chamber of a suitablefluid-bed granulator and preheated up to a product temperature target ofapprox. 36° C.d) Immediately after the product temperature target is reached, the“Granulation Liquid” is sprayed into the mixture for fluid-bedgranulating under dry condition to avoid blocking during granulation.e) At the end of spraying, the resultant granulate is dried at approx.70 C inlet air temperature until the desired LOD value (i.e. 1-2%) isreached.f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0mm.g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) areblended with a suitable blender. Aerosil 200 should be pre-sieved with asmall portion of the sieved granulate through a 0.8 mm-screen beforeuse.h) Magnesium stearate is passed through a 0.8 mm sieve and added intothe granulate. Subsequently the “Final Blend” is produced by finalblending in the free-fall blender.i) The “Final Blend” is compressed into tablets with a rotary press.j) Titanium dioxide, propylene glycol and iron oxide (yellow, red oryellow and red) are dispersed in purified water with a high shearhomo-mixer. Then, hypromellose and talc are added and dispersed with ahomo-mixer and propeller mixer at ambient temperature to produce the“Coating Suspension”.k) The tablet cores are coated with the “Coating Suspension” to thetarget weight gain to produce the “Film-coated Tablets”. The “CoatingSuspension” should be stirred again before use and kept stirring slowlyduring the coating (spraying) process.

Narrative more specific description of an alternative manufacturingprocess for the mono-layer tablets:

-   a) Metformin HCl is sieved using a screen with a mesh size of 0.5    to1 mm before weighing.-   b) L-arginine and copolyvidon are dissolved in purified water at    ambient temperature with a propeller mixer to produce the    “Granulation Liquid”-   c) Metformin HCl and corn starch are heated in a chamber of    fluid-bed granulator at 70-80° C. for more than 15 min until the    product temperature reaches 60° C.-   d) BI 1356 is added into the container, then blended with metformin    HCl and corn starch in the fluid-bed granulator.-   e) The “Granulation Liquid” is sprayed into the mixture for    fluid-bed granulating under dry condition to avoid blocking during    granulation.-   f) At the end of spraying, the resultant granulate is dried at    70-80° C. until the desired LOD value (i.e. 1-2%), in case the LOD    is more than 2%.-   g) The granulate is sieved using a screen with a mesh size of 0.5 to    1.0 mm.-   h) The sieved granulate and colloidal anhydrous silica (Aerosil 200)    are blended with a suitable blender. Aerosil 200 should be sieved    with a 0.5 mm-screen before use.-   i) Magnesium stearate passed through a 0.5 mm sieve and added into    the granulate. Subsequently the “Final Blend” is produced by final    blending in the blender.-   j) The “Final Blend” is compressed into tablets with a rotary press.-   k) Hypromellose and propylene glycol are dissolved in purified water    with a propeller mixer. Talc, titanium dioxide, and iron oxide    (yellow, or yellow and red) are dispersed in purified water with a    homo-mixer. The suspension is added into the hypromellose solution,    then mixed with a propeller mixer at ambient temperature to produce    the “Coating Suspension”.-   l) The tablet cores are coated with the “Coating Suspension” to the    target weight gain to produce the “Film-coated Tablets”. The    “Coating Suspension” should be stirred again before use and kept    stirring slowly during the coating (spraying) process.

2. Bi-Layer Tablet

The composition of bi-layer tablets for a DPP-4 inhibitor of thisinvention (BI 1356)+metformin HCl FDC (Film-coated Tablets) is shown inTable 2.

TABLE 2 Composition of BI 1356 + Metformin HCl FDC Bi-layer Tablets DoseStrength (BI 1356/metformin HCl), mg 2.5/500 2.5/850 2.5/1000 Ingredient[mg] [%] [mg] [%] [mg] [%] BI 1356-portion: (450)    (100)    (450)   (100)    (450)    (100)    BI 1356 2.50  0.556 2.50  0.556 2.50  0.556L-Arginine 2.50  0.556 2.50  0.556 2.50  0.556 D-mannitol 334.75  74.39 334.75  74.39  334.75  74.39  Pregelatinized starch 45.00  10.00  45.00 10.00  45.00  10.00  Corn starch 45.00  10.00  45.00  10.00  45.00 10.00  Copovidone 13.50  3.00 13.50  3.00 13.50  3.00 Magnesium stearate6.75 1.50 6.75 1.50 6.75 1.50 Metformin HCl-portion: (570)    (100)   (969)    (100)    (1140)     (100)    Metformin Hydrochloride 500.0  87.72  850.00  87.72  1000.00   87.72  Corn starch 15.00  2.63 25.50 2.63 30.00  2.63 Copovidone 47.50  8.33 80.57  8.33 95.00  8.33Colloidal Anhydrous Silica 2.50 0.44 4.25 0.44 5.00 0.44 Magnesiumstearate 5.00 0.88 8.50 0.88 10.00  0.88 Total Mass (tablet core)1020    100.00  1419     100.00  1590     100.00  Hypromellose (5 mPa *s) 8.00 50.00  9.50 50.00  11.00  50.00  Propylene glycol 0.80 5.00 0.955.00 1.10 5.00 Talc 2.96 18.50   3.515 18.50  4.07 18.50  Titaniumdioxide 4.00 25.00  4.75 25.00  5.50 25.00  Iron oxide, yellow 0.20 1.25 0.2375 1.25  0.275 1.25 Iron oxide, red 0.04 0.25  0.0475 0.25  0.0550.25 Total Mass (film-coat) 16.00  100.00  19.00  100.00  22.00  100.00 Total Mass (coated tablet) 1036     100.00  1438     100.00  1612    100.00 

Manufacturing Procedure (Bi-Layer Tablets):

DPP-4 inhibitor of this invention (e.g. BI 1356)+metformin HCl FDCbi-layer tablets are produced by a high-shear wet granulation process(for DPP-4 inhibitor-granulate), a fluid-bed granulation process (formetformin HCl-granulate), and bi-layer tableting process with amulti-layer rotary press.

DPP-4 Inhibitor-Granulate:

By using a high-shear granulator the active DPP-4 inhibitor ingredientis pre-mixed with the diluents D-mannitol and pregelatinized starch. Themixture is moistened with granulating liquid, containing purified waterand copovidone as a binder. After further mixing, drying and sieving,the dried granulate is blended with magnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for theBI 1356-granulate:

-   a. Copovidone and L-arginine are dissolved in purified water at    ambient temperature to produce the Granulation Liquid.-   b. BI 1356, mannitol and pregelatinized starch are blended in a    suitable mixer, to produce the Pre-Mix.-   c. The Pre-mix is moistened with the Granulation Liquid and    subsequently granulated.-   d. The moist granulate is sieved through a suitable sieve.-   e. The granulate is dried at about 50° C. (maximum 60° C.) in a    suitable dryer until the desired loss on drying value is obtained.-   f. The dried granulate is sieved through a sieve with a mesh size of    1.0 mm.-   g. Magnesium stearate is passed through a 1.0 mm sieve and added to    the granulate.

Subsequently the “Final Blend A” is produced by final blending in asuitable blender.

Metformin HCl-Granulate:

Metformin HCl and corn starch are pre-treated by heating in a chamber offluid-bed granulator to remove excessive HCl and/or impurity products.After the pre-treatment of metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. After finishing offluid-bed granulation, the granulate is sieved with a suitable screen.The sieved granulate is blended with colloidal anhydrous silica (Aerosil200) and magnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for theMetformin HCl-granulate:

a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1mm before weighing.b) Copolyvidon is dissolved in purified water at ambient temperaturewith a propeller mixer to produce the “Granulation Liquid”c) Metformin HCl and corn starch are heated in a chamber of fluid-bedgranulator at 70-80° C. for more than 15 min until the producttemperature reaches 60° C.d) The “Granulation Liquid” is sprayed into the mixture for fluid-bedgranulating under dry condition to avoid blocking during granulation.e) At the end of spraying, the resultant granulate is dried at 70-80° C.until the desired LOD value (i.e. 1-2%), in case the LOD is more than2%.f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0mm.g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) areblended with a suitable blender. Aerosil 200 should be sieved with a 0.5mm-screen before use.h) Magnesium stearate passed through a 0.5 mm sieve and added into thegranulate.

Subsequently the “Final Blend B” is produced by final blending in theblender.

The “Final Blend A” and “Final Blend B” are compressed into bi-layertablets using a multi-layer rotary press. The tablet cores may befilm-coated by an aqueous film-coating suspension, containinghypromellose as film-forming agent, propylene glycol as plasticizer,talc as glidant and the pigments yellow iron oxide and/or red iron oxideand titanium dioxide.

Narrative more specific description of the manufacturing process for thefilm-coating:

a) Hypromellose and propylene glycol are dissolved in purified waterwith a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow,red or yellow and red) are dispersed in purified water with ahomo-mixer. The suspension is added into the hypromellose solution, thenmixed with a propeller mixer at ambient temperature to produce the“Coating Suspension”.b) The tablet cores are coated with the “Coating Suspension” to thetarget weight gain to produce the “Film-coated Tablets”. The “CoatingSuspension” should be stirred again before use and kept stirring slowlyduring the coating (spraying) process.

3. Tablet-in-Tablet or Bull's Eye Tablet

The composition of Tablet-in-Tablet or Bull's eye tablets for a DPP-4inhibitor of this invention (BI 1356)+metformin HCl FDC (Film-coatedTablets) is shown in Table 3.

TABLE 3 Composition of BI 1356 + Metformin HCl FDC Tablet-in-Tablet orBull's Eye Tablets Dose Strength (BI 1356/metformin HCl), mg 2.5/5002.5/850 2.5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%] BI 1356-portion:(45)    (100)    (45)    (100)    (45)    (100)    BI 1356 2.50 5.562.50 5.56 2.50 5.56 L-Arginine 1.00 2.22 1.00 2.22 1.00 2.22 D-mannitol30.475 67.72  30.475 67.72  30.475 67.72  Pregelatinized starch 4.5010.00  4.50 10.00  4.50 10.00  Corn starch 4.50 10.00  4.50 10.00  4.5010.00  Copovidone  1.350 3.00  1.350 3.00 1.35 3.00 Magnesium stearate 0.675 1.50  0.675 1.50 6.75 1.50 Metformin HCl-portion: (570)   (100)    (969)    (100)    (1140)     (100)    Metformin Hydrochloride500.0   87.72  850.00  87.72  1000.00   87.72  Corn starch 15.00  2.6325.50  2.63 30.00  2.63 Copovidone 47.50  8.33 80.57  8.33 95.00  8.33Colloidal Anhydrous Silica 2.50 0.44 4.25 0.44 5.00 0.44 Magnesiumstearate 5.00 0.88 8.50 0.88 10.00  0.88 Total Mass (tablet core) 615   100.00  1014     100.00  1185     100.00  Hypromellose (5 mPa * s) 6.0050.00  8.00 50.00  9.00 50.00  Propylene glycol 0.60 5.00 0.80 5.00 0.905.00 Talc 2.22 18.50  2.96 18.50  3.33 18.50  Titanium dioxide 3.0025.00  4.00 25.00  4.50 25.00  Iron oxide, yellow 0.15 1.25 0.20 1.25 0.225 1.25 Iron oxide, red 0.03 0.25 0.04 0.25  0.045 0.25 Total Mass(film-coat) 12.00  100.00  16.00  100.00  18.00  100.00  Total Mass(coated tablet) 627    100.00  1030     100.00  1203     100.00 

Manufacturing Procedure (Tablet-in-Tablet or Bull's Eye Tablet):

DPP-4 inhibitor of this invention (e.g. BI 1356)+metformin HCl FDCTablet-in-Tablet or Bull's eye tablets are produced by a high-shear wetgranulation process (for DPP-4 inhibitor-granulate), a rotary press (forDPP-4 inhibitor core-tablet), a fluid-bed granulation process (formetformin HCl-granulate), and press-coating process with a press-coater.

DPP-4 Inhibitor Core-Tablet:

By using a high-shear granulator the active DPP-4 inhibitor ingredientis pre-mixed with the diluents D-mannitol and pregelatinized starch. Themixture is moistened with granulating liquid, containing purified waterand copovidone as a binder. After further mixing, drying and sieving,the dried granulate is blended with magnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for theBI 1356 core-tablets:

-   a. Copovidone and L-arginine are dissolved in purified water at    ambient temperature to produce the Granulation Liquid.-   b. BI 1356, mannitol and pregelatinized starch are blended in a    suitable mixer, to produce the Pre-Mix.-   c. The Pre-mix is moistened with the Granulation Liquid and    subsequently granulated.-   d. The moist granulate is sieved through a suitable sieve.-   e. The granulate is dried at about 50° C. (maximum 60° C.) in a    suitable dryer until the desired loss on drying value is obtained.-   f. The dried granulate is sieved through a sieve with a mesh size of    1.0 mm.-   g. Magnesium stearate is passed through a 1.0 mm sieve and added to    the granulate. Subsequently the “Final Blend” is produced by final    blending in a suitable blender.-   h. “Final Blend” is compressed into “BI 1356 core-tablets” with a    rotary press.

Metformin HCl-Granulate:

Metformin HCl and corn starch are pre-treated by heating in a chamber offluid-bed granulator to remove excessive HCl and/or impurity products.After the pre-treatment of metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. After finishing offluid-bed granulation, the granulate is sieved with a suitable screen.The sieved granulate is blended with colloidal anhydrous silica (Aerosil200) and magnesium stearate as a lubricant.

Narrative more specific description of the manufacturing process for theMetformin HCl-granulate:

a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1mm before weighing.b) Copolyvidon is dissolved in purified water at ambient temperaturewith a propeller mixer to produce the “Granulation Liquid”c) Metformin HCl and corn starch are heated in a chamber of fluid-bedgranulator at 70-80° C. for more than 15 min until the producttemperature reaches 60° C.d) The “Granulation Liquid” is sprayed into the mixture for fluid-bedgranulating under dry condition to avoid blocking during granulation.e) At the end of spraying, the resultant granulate is dried at 70-80° C.until the desired LOD value (i.e. 1-2%), in case the LOD is more than2%.f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0mm.g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) areblended with a suitable blender. Aerosil 200 should be sieved with a 0.5mm-screen before use.h) Magnesium stearate passed through a 0.5 mm sieve and added into thegranulate. Subsequently “Metformin HCl-granulate” (Final Blend) isproduced by final blending in the blender.

The “DPP-4 inhibitor core-tablets” and “Metformin HCl-granulate” arecompressed into Tablet-in-Tablet or Bull's eye tablets using apress-coater. The difference between the Tablet-in-Tablet and Bull's eyetablet is the position of the core tablet.

Narrative more specific description of the manufacturing process for theTablet-in-Tablet:

a) Fill a half of Metformin HCl-granulate in a die.b) Place a BI 1356 core-tablet on the surface of MetforminHCl-granulate.c) Cover the core-tablet with second half of Metformin HCl-granulate,then compressed into the tablet (Tablet-in-Tablet).

Narrative more specific description of the manufacturing process for theBull's eye tablets:

a) Fill Metformin HCl-granulate in a die.

b) Place the BI 1356 core-tablet on the Metformin HCl-granulate in thedie, then compressed into the tablet (Bull's eye tablet).

The tablets may be film-coated by an aqueous film-coating suspension,containing hypromellose as film-forming agent, propylene glycol asplasticizer, talc as glidant and the pigments yellow iron oxide and/orred iron oxide and titanium dioxide.

Narrative more specific description of the manufacturing process for thefilm-coating:

a) Hypromellose and propylene glycol are dissolved in purified waterwith a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow,red or yellow and red) are dispersed in purified water with ahomo-mixer. The suspension is added into the hypromellose solution, thenmixed with a propeller mixer at ambient temperature to produce the“Coating Suspension”.b) The tablet cores are coated with the “Coating Suspension” to thetarget weight gain to produce the “Film-coated Tablets”. The “CoatingSuspension” should be stirred again before use and kept stirring slowlyduring the coating (spraying) process.

4. DPP-4 Inhibitor—Drug Layering on Metformin HCl Tablet (Film-Coatingfor Drug-Loading)

The composition of a DPP-4 inhibitor of this invention (BI1356)+metformin HCl FDC (Film-coated Tablets) which are prepared by drugloading by film-coating on the Metformin HCl Tablet is shown in Table 4.

TABLE 4 Composition of BI 1356 + Metformin HCl FDC BI 1356-Coating onMetformin HCl Tablet Dose Strength (BI 1356/metformin HCl), mg 2.5/5002.5/850 2.5/1000 Ingredient [mg] [%] [mg] [%] [mg] [%] MetforminHCl-portion: (570)    (100)    (969)    (100)    (1140)     (100)   Metformin Hydrochloride 500.0   87.72  850.0   87.72  1000.0   87.72 Corn starch 15.0  2.63 25.5  2.63 30.0  2.63 Copovidone 47.5  8.3380.57  8.33 95.0  8.33 Colloidal Anhydrous Silica 2.5  0.44 4.25 0.445.0  0.44 Magnesium stearate 5.0  0.88 8.5  0.88 10.0  0.88 Total Mass(tablet core) 570    100.00  969    100.00  1140     100.00  Seal-coat(seal-coating): (12)    (100)    (16)    (100)    (18)    (100)   Hypromellose (5 mPa * s) 6.00 50.00  8.00 50.00  9.00 50.00  Propyleneglycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc 2.22 18.50  2.96 18.50  3.3318.50  Titanium dioxide 3.00 25.00  4.00 25.00  4.50 25.00  Iron oxide,yellow 0.15 1.25 0.20 1.25  0.225 1.25 Iron oxide, red 0.03 0.25 0.040.25  0.045 0.25 Drug-layer (drug-loading): (25)    (100)    (25)   (100)    (25)    (100)    BI 1356 2.50 10.00  2.50 10.00  2.50 10.00 L-Arginine 2.50 10.00  2.50 10.00  2.50 10.00  Hypromellose (5 mPa * s)18.00  72.00  18.00  72.00  18.00  72.00  Propylene glycol 2.00 8.002.00 8.00 2.00 8.00 Over-coat (over-coating): (12)    (100)    (16)   (100)    (18)    (100)    Hypromellose (5 mPa * s) 6.00 50.00  8.0050.00  9.00 50.00  Propylene glycol 0.60 5.00 0.80 5.00 0.90 5.00 Talc2.22 18.50  2.96 18.50  3.33 18.50  Titanium dioxide 3.00 25.00  4.0025.00  4.50 25.00  Iron oxide, yellow 0.15 1.25 0.20 1.25  0.225 1.25Iron oxide, red 0.03 0.25 0.04 0.25  0.045 0.25 Total Mass (film-coat)49    100.00  57    100.00  61    100.00  Total Mass (coated tablet)619    100.00  1026     100.00  1201     100.00 

Manufacturing Procedure (DPP-4 Inhibitor-Drug Layering by Film-Coatingon Metformin HCl Tablet):

DPP-4 inhibitor (e.g. BI 1356)+metformin HCl FDC with drug coating isproduced by a fluid-bed granulation process, a conventional tabletingprocess, and film-coating process with three steps: seal-coating,drug-loading and over-coating. The over-coating may be able to beskipped by combining with the drug-loading, if the stability isacceptable.

Metformin HCl Tablets:

Metformin HCl and corn starch are pre-treated by heating in a chamber offluid-bed granulator to remove excessive HCl and/or impurity products.After the pre-treatment of metformin HCl and corn starch, fluid-bedgranulation is conducted by spraying of “Granulation Liquid” composed ofcopolyvidon (Kollidon VA64) and purified water. After finishing offluid-bed granulation, the granulate is sieved with a suitable screen.The sieved granulate is blended with colloidal anhydrous silica (Aerosil200) and magnesium stearate as a lubricant. The final blend iscompressed into the tablets with a conventional rotary press.

Narrative more specific description of the manufacturing process for theMetformin HCl-granulate:

a) Metformin HCl is sieved using a screen with a mesh size of 0.5 to 1mm before weighing.b) Copolyvidon is dissolved in purified water at ambient temperaturewith a propeller mixer to produce the “Granulation Liquid”c) Metformin HCl and corn starch are heated in a chamber of fluid-bedgranulator at 70-80° C. for more than 15 min until the producttemperature reaches 60° C.d) The “Granulation Liquid” is sprayed into the mixture for fluid-bedgranulating under dry condition to avoid blocking during granulation.e) At the end of spraying, the resultant granulate is dried at 70-80° C.until the desired LOD value (i.e. 1-2%), in case the LOD is more than2%.f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0mm.g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) areblended with a suitable blender. Aerosil 200 should be sieved with a 0.5mm-screen before use.h) Magnesium stearate passed through a 0.5 mm sieve and added into thegranulate. Subsequently “Final Blend” is produced by final blending inthe blender.i) The “Final Blend” is compressed into the tablets with a conventionalrotary press.

Film-Coating:

The tablets are film-coated by (1) seal-coating: by an aqueousfilm-coating suspension, containing hypromellose as film-forming agent,propylene glycol as plasticizer, talc as glidant and the pigments yellowiron oxide and/or red iron oxide and titanium dioxide, (2) drug-loading:by an aqueous film-coating suspension, containing hypromellose asfilm-forming agent, propylene glycol as plasticizer, BI 1356 as drugsubstance, and L-arginine as stabilizer, and (3) over-coating: by anaqueous film-coating suspension, containing hypromellose as film-formingagent, propylene glycol as plasticizer, talc as glidant and the pigmentsyellow iron oxide and/or red iron oxide and titanium dioxide,

Narrative more specific description of the manufacturing process for thefilm-coating with a coating machine:

a) Hypromellose and propylene glycol are dissolved in purified waterwith a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow,red or yellow and red) are dispersed in purified water with ahomo-mixer. The suspension is added into the hypromellose solution, thenmixed with a propeller mixer at ambient temperature to produce the“Coating Suspension” for “seal-coating” and “over-coating”.b) Hypromellose, propylene glycol and L-arginine are dissolved inpurified water with a propeller mixer. BI 1356 (active drug) is addedinto the hypromellose solution, then dispersed with a propeller mixer atambient temperature to produce the “Drug Suspension” for “drug-loading”.c) The Metformin HCl tablets are coated with the “Coating Suspension” tothe target weight gain to form the “seal-coat”. The “Coating Suspension”should be stirred again before use and kept stirring slowly during thecoating (spraying) process.d) Following the seal-coating, the “Drug Suspension” is applied to thesurface of the Metformin HCl tablets to form the “drug layer” (drugloading). The “Drug Suspension” should be stirred again before use andkept stirring slowly during the coating (spraying) process. The coatingend point can be determined by available PAT (Process AnalysisTechnology).e) After drug loading the “Coating Suspension” is applied to the BI 1356drug-loaded tablets to form the “over-coat” and to produce the“Film-coated Tablets”. The “Coating Suspension” should be stirred againbefore use and kept stirring slowly during the coating (spraying)process.

Product Description:

The product description of BI 1356+Metformin HCl FDC mono-laver tablets(tablet core and film-coated tablets) is shown in Table 8 and Table 9,respectively.

TABLE 8 Product Description of BI 1356 + Metformin HCl FDC Mono-layerTablets (Tablet Core) Dose Strength (BI 1356/metformin HCl), mg Items2.5/500 2.5/850 2.5/1000 Tablet shape Oval, Oval, Oval, biconvexbiconvex biconvex Tablet size [mm] 16.2 × 8.5 19.1 × 9.3 21.0 × 9.6Color white Weight 590 1000 1180 Thickness [mm], (Mean) Approx. 5.8Approx. 7.3 Approx. 7.6 Crushing strength [N], ≧100, ≧150, ≧150, (Mean)Approx. 140 Approx. 190 Approx. 200 Disintegration time [min] ≦15 ≦15≦15 Friability [%] ≦0.5 ≦0.5 ≦0.5

TABLE 9 Product Description of BI 1356 + Metformin HCl FDC Mono-layerTablets (Coated) Dose Strength (BI 1356/metformin HCl), mg Items 2.5/5002.5/850 2.5/1000 Color light yellow light orange light red Weight 6021016 1198 Thickness [mm], (Mean) Approx. 5.9 Approx. 7.4 Approx. 7.7Crushing strength [N] (Mean) ≧100, ≧150, ≧150, Approx. 180 Approx. 240Approx. 250 Disintegration time [min] ≦15 ≦15 ≦15

Stability Data:

Stability data of BI 1356+Metformin HCl FDC mono-laver tablets (tabletcore) with or without L-arginine is shown in the following tables (over2 weeks, 1 month and 3 months):

2.5+500 mg tablets+12.5 mg arginine:

60° C. glass bottle Test parameter Initial 2 W 1M 3M Degradation BI 1356(%) <0.2 <0.2 <0.2 <0.2 Total2.5+500 mg tablets+0 mg arginine:

60° C. glass bottle Test parameter Initial 2 W 1M 3M Degradation BI 1356(%) <0.2 1.1 2.9 8.5 Total2.5+1000 mg tablets+25 mg arginine:

60° C. glass bottle Test parameter Initial 2 W 1M 3M Degradation BI 1356(%) <0.2 <0.2 <0.2 0.2 Total2.5+1000 mg tablets+0 mg arginine:

60° C. glass bottle Test parameter Initial 2 W 1M 3M Degradation BI 1356(%) <0.2 1.9 4.7 13.6 TotalBI 1356, a Potent and Selective DPP-4 Inhibitor, is Safe and Efficaciousin Patients with Inadequately Controlled Type 2 Diabetes DespiteMetformin Therapy

Efficacy and safety of BI 1356 (1, 5, or 10 mg qd), a potent andselective dipeptidyl peptidase-4 (DPP-4) inhibitor, was examined ininadequately controlled, metformin-treated (MET, ≧1 g daily) type 2diabetic patients (T2DM; HbA1c at baseline 7.5-10.0%). Effects werecompared to add-on of placebo (PBO) or of open label glimepiride (GLIM;1 to 3 mg qd) in a 12-week randomized, double-blind study. Antidiabeticmedication other than metformin was washed out for 6 weeks (34.7% of thepatients).

The primary endpoint was change from baseline in HbA1c, adjusted forprior antidiabetic medication. 333 patients (mean baseline HbA1c 8.3%;fasting plasma glucose [FPG] 185 mg/dL) were randomized to BI 1356, PBOor open-label GLIM. After 12 weeks, BI 1356 treatment resulted insignificant placebo corrected mean reductions in HbA1c (BI 1356 1 mg,n=65, −0.39%; 5 mg, n=66, −0.75%; 10 mg, n=66, −0.73%). Patientsreceiving GLIM demonstrated a slightly greater mean PBO correctedreduction in HbA1c at Week 12 (n=64,-0.90%). Reductions in FPG frombaseline to Week 12 with BI 1356 were statistically significant (1 mg,−19 mg/dL; 5 mg, −35 mg/dL; 10 mg, −30 mg/dL). Hence, a dose-responserelationship was demonstrated for HbA1c and FPG, reaching an effectplateau at 5 mg of BI 1356. For this dose, >80% DPP-4 inhibition attrough in >80% of the patients at week 12 was achieved.

In total, 106 patients (43.1%) experienced adverse events (AEs) withsimilar incidences across all treatments. Most frequently reportedepisodes were nasopharyngitis (7.5%), diarrhoea (3.3%), and nausea(3.0%). Drug-related hypoglycaemia did not occur with BI 1356 or PBO butin 3 patients receiving GLIM. Ten patients (3.7%) experienced seriousAEs but none of these events were considered drug-related.

The addition of BI 1356 to MET in patients with T2DM inadequatelycontrolled on MET alone achieved clinically relevant and statisticallysignificant reductions in HbA1c. Combination treatment with BI 1356 1,5, and 10 mg and MET was well tolerated and no case of hypoglycaemia wasreported. The incidence of AEs was comparable with BI 1356 and PBO.

Efficacy and Safety of Linagliptin in Type 2 Diabetes InadequatelyControlled on Metformin Monotherapy

A multi-center, 24-week, randomized, placebo-controlled, double-blind,parallel group study examines the efficacy and safety of linagliptin(LI) administered as add-on therapy to metformin (MET) in type 2diabetes mellitus (T2DM) hyperglycemic patients with insufficientglycemic control (HbA1c≧7 to ≦10.0% for patients previously treated onlywith metformin, or ≧6.5 to ≦9.0% for patients previously treated withadditional oral antihyperglycemic drugs). Subjects who enter thescreening period discontinue previous antidiabetic medication other thanMET (≧1500 mg/day) for 6 weeks (including a placebo (PBO) run-in periodduring the last 2 weeks) prior to randomization to LI (n=524) or PBO(n=177). Mean baseline characteristics and demographics (HbA1c, 8.1%;fasting plasma glucose [FPG], 168.8 mg/dL; age, 56.5 yrs; BMI, 29.9kg/m2) are similar between groups. The primary endpoint is the changefrom baseline HbA1c after 24 weeks of treatment, evaluated with ananalysis of covariance (ANCOVA) adjusted for baseline HbA1c and priorantidiabetic medication. After 24 weeks of treatment, the adjusted meantreatment difference between LI+MET and PBO+MET is −0.64% (p<0.0001) infavor of LI+MET for change in HbA1c (%). Patients with a baseline HbA1cof ≧7.0% who receive LI+MET are more likely to achieve an HbA1c ≦7.0%relative to those receiving placebo+MET (26.2% vs. 9.2%, respectively;odds ratio, 4.4; p=0.0001). At week 24 LI+MET is superior to PBO+MET inreducing the mean fasting plasma glucose (FPG) from baseline (−21.1mg/dL; p<0.0001). At study-end, 2 hr post-prandial glucose (PPG)analyzed in meal tolerance tests shows a significantly greater(p<0.0001) mean reduction from baseline for the LI+MET treated (−67.1mg/dL) versus the PBO+MET group. The proportion of patients reporting atleast one adverse event (AE) is comparable within the LI+MET and PBO+METgroups (52.8% and 55.4%, respectively). Hypoglycemia is rare, occurringin 5 PBO+MET patients (2.8%) and 3 LI+MET patients (0.6%), all episodesbeing of mild intensity. The change in the body weight from baseline to24 weeks is similar between the 2 treatment groups (−0.5 kg PBO+MET;−0.4 kg LI+MET). Conclusion, linagliptin 5 mg qd as add-on therapy inpatients with T2DM inadequately controlled on metformin is welltolerated and produces significant and clinically meaningfulimprovements in glycemic control (reductions in HbA1c, FPG and 2 h PPGwithout weight gain). Linagliptin as add-on therapy to metformin inpatients with T2DM and insufficient glycemic control is well toleratedwith the incidence of adverse events comparable to placebo.

Linagliptin improves Glycemic Control in Asian Type 2 Diabetes PatientsInadequately Controlled on Metformin Monotherapy

A multi-center, 24-wk, placebo (PBO)-controlled study examines efficacyand safety of the DPP-4 inhibitor linagliptin (LI) (5 mg qd) as add-onto metformin (MET) therapy in T2DM patients (pts) with insufficientglycemic control. All pts (HbA1c ≧7 to ≦10.0% if previously treated withMET, or ≧6.5 to 9.0% if treated with another oral antihyperglycemic drug[OAD]) discontinue OADs other than MET (1500 mg/day) for 6 wks(including a PBO run-in period during the last 2 wks) beforerandomization to LI+MET (n=524; of which n=111 were Asian) or PBO+MET(n=177; n=32 Asian). At wk 24, the PBO-adjusted mean treatmentdifference in HbA1c in the Asian pts is −0.86% (P<0.0001) in favor ofLI+MET. The difference in the adjusted mean change from baseline (BL) atwk 24 for fasting plasma glucose is −21 mg/dL for the full analysis set(FAS) pts on LI+MET (P<0.0001). 2 h post-prandial glucose (PPG) analyzedin meal tolerance tests, shows a reduction from BL of −67 mg/dL forLI+MET FAS pts (P<0.0001) at wk 24. Numbers of pts reporting at least 1adverse event are comparable for the LI (52.8%) and PBO (55.4%) groups(treated set). Hypoglycemia is rare (0.6% of LI pts; 2.8% of PBO pts).Linagliptin as add-on therapy in pts with T2DM inadequately controlledon MET delivers significant and clinically meaningful reductions inHbA1c, FPG and 2hPPG without weight gain. In the Asian patient subgroupLinagliptin significantly improves glycemic control.

Linagliptin Improves Glycemic Control in Asian Type 2 Diabetes PatientsInadequately Controlled on Metformin and Sulfonylurea Dual CombinationTherapy

A multi-center, 24-wk, placebo (PBO)-controlled study examines theefficacy and safety of the oral DPP-4 inhibitor linagliptin (LI; 5 mgqd) in type 2 diabetes (T2DM) patients (pts) with insufficient glycemiccontrol (HbA1c to 10.0%) on the combination of metformin (MET) plussulfonylurea (SU). All pts have a 2-wk PBO run-in before randomizationto LI+MET+SU (n=793; of which n=397 are Asian) or PBO+MET+SU (n=265;n=141 Asian). Pts from China (193, 18%) and Korea (174, 16%) make up thehighest numbers of Asian race pts enrolled. At wk 24, the PBO-adjustedmean treatment difference in HbA1c in the Asian pts is −0.71% (P<0.0001)in favor of LI+MET+SU. For the full analysis set (FAS), the adjustedmean difference between LI and PBO for the change in fasting plasmaglucose (FPG) from baseline at wk 24 is −13 mg/dL (P<0.0001). Measuresof β-cell function (HOMA-% B) and insulin resistance (HOMA-IR) improvewith LI vs. PBO pts in the FAS (P<0.05). Reported severe adverse events(AEs) are low for LI+MET+SU (2.4%) and PBO+MET+SU (1.5%) pts (treatedset). No significant changes in weight are noted (FAS). Linagliptinadd-on to MET and SU combination therapy has a favorable safety andtolerability profile and is weight neutral. This combinationsignificantly improves glycemic control in T2DM pts, including Asianpts. A low risk for hypoglycemia should be considered when linagliptinis indicated as add-on to pre-existing sulfonylurea therapy. Linagliptinprovides an additional option prior to insulin therapy in patients forwhom glycemia is insufficiently controlled with metformin plus asulfonylurea agent.

1. A method of treating type 2 diabetes mellitus and conditions relatedthereto in a patient in need of such treatment, comprising administeringto the patient a coated tablet a comprising1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinein a dosage strength of 2.5 mg and having a particle size distributionof 0.1 μm<X90<200 μm, metformin hydrochloride in an amount of 500 mg,850 mg, or 1000 mg, L-arginine, and a filler which is corn starch, abinder which is copovidone, a glidant which is colloidal anhydroussilica, and a lubricant which is magnesium stearate; wherein the amountof1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinecomprised is 0.1% to 0.42% by weight of the coated tablet; optionally incombination with one or more other active substances; wherein thepatient is either (a) a type 2 diabetes patient who has not beenpreviously treated with an antihyperglycemic agent, or (b) a type 2diabetes patient with insufficient glycemic control despite therapy withone or two conventional antihyperglycemic agents selected from the groupconsisting of metformin, sulphonylureas, thiazolidinediones, glinides,alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and insulin orinsulin analogues, wherein the tablet provides for immediate release ofthe metformin hydrochloride, and the tablet is administered twice dailyto the patient.
 2. The method according to claim 1, which is forimproving glycemic control in said type 2 diabetes patient who has notbeen previously treated with an antihyperglycemic agent.
 3. The methodaccording to claim 1, which is for improving glycemic control in saidtype 2 diabetes patient with insufficient glycemic control despitemono-therapy with metformin.
 4. The method according to claim 1, whereinsaid solid pharmaceutical composition is administered in combinationwith a thiazolidinedione, which is for improving glycemic control insaid type 2 diabetes patient with insufficient glycemic control despitedual combination therapy with metformin and a thiazolidinedione.
 5. Themethod according to claim 1, wherein said solid pharmaceuticalcomposition is administered in combination with a sulphonylurea, whichis for improving glycemic control in said type 2 diabetes patient withinsufficient glycemic control despite dual combination therapy withmetformin and a sulphonylurea.
 6. The method according to claim 1,wherein L-arginine is present from about 1 mg to about 50 mg.
 7. Themethod according to claim 1, wherein the1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineand L-arginine are present in a weight ratio from about 1:20 to about10:1.
 8. The method according to claim 1, wherein the tablet is amonolayer tablet which further comprises a film coat.
 9. The methodaccording to claim 8, wherein the film-coat comprises a film-coatingagent which is hypromellose; a plasticizer which is propylene glycol;optionally a glidant which is talc; and optionally one or more pigmentsselected from titanium dioxide, iron oxide red and iron oxide yellow.10. The method according to claim 1, wherein the pharmaceuticalcomposition is an immediate release dosage form, characterized in thatin a dissolution test after 45 minutes at least 75% by weight of each ofthe active ingredients is dissolved.
 11. The method of claim 1, whereinthe1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinehas a particle size distribution of 5 μm≦X90≦200 μm.